The investigation focused on the Y402H polymorphism in CFH, a gene whose protein regulates the alternative complement pathway. Individuals homozygous for the risk-associated C allele have previously been reported to have a five- to sevenfold higher risk of AMD than those with the protective TT genotype. The variant lies in a ligand-binding region of factor H and is thought to reduce the protein’s ability to attach to polyanionic surfaces such as Bruch’s membrane. Reduced regulation can permit persistent complement activation and the generation of inflammatory fragments, including C5a. Those fragments can recruit immune cells and stimulate inflammatory responses, but the work reported here asks how a locally active protease might connect complement dysregulation to remodeling of extracellular matrix in the retina and choroid.

To investigate systemic granzyme B concentrations, the researchers examined people with dry AMD and compared them with a younger, non-AMD reference group. Both age-matched AMD genotype groups had higher mean plasma concentrations than the younger controls: 89.49 pg/mL with SEM 23.65 for the CC group and 64.48 pg/mL with SEM 24.35 for the TT group, compared with 22.3 pg/mL with SEM 7.5 in controls. The difference between the two AMD genotypes was not statistically significant in a Mann–Whitney U test. This result did not identify a systemic marker that distinguished the two genotypes, and the comparison does not establish when or where the genotype-associated tissue changes begin. Small sample numbers, including eight participants in each AMD group, limit the strength and generalizability of the plasma comparison, while the age difference between the AMD and control cohorts prevents treating the systemic increase as a genotype-specific effect.

The clearest human findings came from immunofluorescence analysis of non-AMD donor eyes. Five eyes with the high-risk CC genotype were compared with five age-matched protective TT eyes. Choroidal mast-cell density was significantly higher in the CC group, as was the density of mast cells expressing granzyme B. Granzyme B-positive mast cells averaged 4.2 cells per 0.1 square millimeter in CC eyes, compared with 1.9 cells per 0.1 square millimeter in TT eyes. The difference in degranulating mast-cell density only approached the threshold for statistical significance, at p = 0.0635, so the result should not be described as a demonstrated difference in degranulation across the groups. Nevertheless, high-magnification images showed extracellular granzyme B and tryptase granules around a degranulating cell in one CC eye, while dual labeling indicated that 87% of resident choroidal mast cells coexpressed the two proteins. A subset of granzyme B-positive cells, averaging 24.2% when the groups were combined, was tryptase-negative, consistent with other immune sources being present. The tissue evidence therefore supports mast cells as a major local source of granzyme B in this experimental context.

Vitronectin supplied a possible functional link between extracellular granzyme B and complement regulation. An in vitro cleavage assay demonstrated that active granzyme B could generate specific vitronectin fragments after incubation with the protein. In human donor tissue, protective TT eyes displayed strong vitronectin immunoreactivity along Bruch’s membrane and throughout the choriocapillaris and Sattler’s layer, whereas the inner choroid of high-risk CC eyes showed significantly less staining, with a reported p value of 0.0144. CC eyes also more often contained vitronectin concentrated in sub-retinal pigment epithelial deposits, while TT eyes had fewer and smaller deposits consistent with age-related change. The observations indicate redistribution as well as depletion. They are consistent with the proposed model that proteolysis removes soluble or matrix-associated vitronectin while leaving aggregation-prone material near the retinal pigment epithelium, although the tissue study alone cannot prove that granzyme B directly caused the pattern in donors.

The contribution of granzyme B was tested more directly in aged mice. The researchers compared 13- to 17-month-old granzyme B knockout animals with age-matched wild-type C57BL/6 mice, with four animals in each group. Choroidal vitronectin staining was generally faint in wild-type eyes but robust in knockout eyes, particularly around the choriocapillaris and larger choroidal blood vessels. Quantified signal was significantly higher in knockout tissue, at p = 0.0007. This animal comparison supports a role for endogenous granzyme B in regulating or turning over perivascular vitronectin. It does not reproduce the complete human genetic-risk environment, and the knockout establishes the influence of granzyme B on vitronectin abundance more directly than it establishes an AMD phenotype or a treatment effect. The study also does not determine whether elevated granzyme B alone is sufficient to produce the human pattern.

If granzyme B reduces functional vitronectin, complement inhibition should decline and the terminal membrane attack complex should accumulate. The human tissue analysis produced a corresponding pattern. Protective TT eyes had minimal, patchy staining for C5b-9, the membrane attack complex also known as MAC, whereas CC eyes showed prominent deposits around the choriocapillaris and at the interface between Bruch’s membrane and the retinal pigment epithelium. Quantitative analysis confirmed higher MAC immunoreactivity in the high-risk group, with a reported p value of 0.0079. These findings extend previous observations of increased choroidal MAC in high-risk CFH genotypes. Together, the lower vitronectin signal and higher MAC deposition support impaired local complement control, although the cross-sectional donor data cannot establish the temporal order of the two events in an individual eye. The findings also do not show that MAC deposition caused the observed mast-cell infiltration or vitronectin redistribution.

Cell experiments offered a potential explanation for how complement signaling initiates the pathway. Exposure of ARPE-19 retinal pigment epithelial cells to 5 micrograms per milliliter of C5a for 24 hours significantly increased expression of GZMB, TNFα and IL8 messenger RNA, with reported p values of 0.024, 0.0007 and 0.007, respectively. ELISA measurements showed that granzyme B protein remained at similar levels within cell lysates but increased significantly in culture supernatants after stimulation, with a reported p value of 0.0006. The result distinguished increased secretion from increased intracellular storage. C5a-treated cells also showed disruption of the continuous hexagonal pattern of the tight-junction protein ZO-1 after 48 hours, with intracellular accumulation of the protein and fewer cells retaining an intact barrier; the difference in cells displaying intact staining had a reported p value of 0.0037. These findings provide direct experimental evidence that C5a can stimulate granzyme B release and stress RPE cultures. As a simplified culture system, however, ARPE-19 cells do not reproduce the full immune, vascular and extracellular environment of a human eye.

Bulk RNA sequencing of ARPE-19 cells exposed to 100 nanomolar granzyme B for 18 hours identified 1,464 differentially expressed genes. A volcano plot displayed a twofold-change threshold, while a separate greater-than-1.5-fold criterion was applied to the selected epithelial, vascular, barrier, immune, stress and trophic genes shown in the detailed analysis. RPE identity markers RBP1, TJP1 and BEST1 remained stable across control and stimulated groups, but functional enrichment pointed to tissue morphogenesis, epithelial differentiation and vasculature development. Some structural and cell-fate genes increased, including GJA1, PPL, BMP4 and ID3, while CCN2, VEGFA and EDN1 declined. Damage-sensing and stress-associated genes, including TLR3, IL-33 and CYP1B1, increased, while several broad inflammatory or survival cytokines were reduced. The pattern is compatible with attempted barrier compensation alongside diminished vascular and trophic support, but transcriptional signatures alone do not demonstrate retinal atrophy or predict its development in patients.

Collectively, the experiments support a model in which the CFH Y402H risk genotype is linked to chronic complement activation, increased C5a signaling, granzyme B release by RPE cells and infiltrating mast cells, and extracellular remodeling. Cleaved vitronectin may then provide less inhibition of membrane attack complex assembly while contributing to sub-RPE deposits, creating conditions associated with early tissue changes. The study also notes that prior work found granzyme B can cleave C5 to generate active C5a, raising the possibility of a self-reinforcing loop, although that specific feedback mechanism was not directly tested here. Postmortem tissue, limited donor numbers, unequal control ages, the inability to assess biological-sex effects and the reduced fidelity of cell culture and mouse models constrain interpretation. The work identifies extracellular granzyme B as a mechanistic link and a potential therapeutic target, but it does not demonstrate that inhibiting it would prevent AMD or protect vision in patients.

Subject of Research: Granzyme B, vitronectin cleavage and complement dysregulation in early age-related macular degeneration

Article Title: Factor H polymorphism elevates granzyme B and impairs complement inhibition in human and mouse models

Article References: Chakravarthy, H., Xi, J., Yoo, H.-S., Buss, A., Li, B., Bell, R., Haegert, A., Le Bihan, S., Granville, D. J., & Matsubara, J. A. (2026). Factor H polymorphism elevates granzyme B and impairs complement inhibition in human and mouse models. iScience, 29(11), Article 117957. https://doi.org/10.1016/j.isci.2026.117957

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117957

Keywords: age-related macular degeneration, CFH Y402H, complement factor H, granzyme B, vitronectin, membrane attack complex, retinal pigment epithelium, choroidal mast cells, extracellular matrix, C5a, Factor, polymorphism

Investigators also reanalysed permanent slides from two Far Eastern populations and two samples collected at Berdsky Pond in Novosibirsk Province in 1985, because the original publication did not provide sufficiently comprehensive data for quantitative analysis. Published data were incorporated for 10 additional populations, bringing the total to 41. Where larvae were collected repeatedly at the same site, the researchers tested for differences in banding-sequence frequencies among sampling years and combined the samples when no significant differences were found.

Species identification was based on larval morphology and polytene chromosomes from the salivary glands. Chromosome arms were mapped using established systems for the Chironomus plumosus species group, and banding sequences were classified as main, alternative, rare or unique. Quantitative analyses used populations represented by at least 10 specimens, and all populations were checked for deviations from Hardy–Weinberg equilibrium.

Only the RAL-MA population showed a deviation, involving more heterozygotes for the arm D combination p’borD1.h’borD2 than expected. Chironomus borokensis has a haploid chromosome number of four, with the arms arranged as AB, CD, EF and G. Chromosomes I and II are metacentric, chromosome III is submetacentric and chromosome IV is telocentric.

Inversion polymorphism occurred in every chromosomal arm, and the study expanded the species’ known banding-sequence pool to 40. The largest number recorded from a single collection date was 18, while one population record contained 23 sequences when observations from multiple years were combined. Six alternative banding sequences across five chromosomal arms met the study’s criteria: h’borA2 and p’borA4 in arm A, h’borB2 in arm B, h’borD2 in arm D, p’borF2 in arm F, and p’borG2 in arm G.

Each was present at high frequency in at least some populations and occurred in both heterozygous and homozygous states. The frequency of p’borG2 reached 100% in many Western Siberian populations. Rare sequences in arms A and F were p’borA5, p’borA8, p’borA9 and h’borF4.

The sequence p’borA5 is a complex inversion that differs from the main arm A sequence by three inversion steps. The authors inferred that it predates the divergence of C. borokensis because an identical sequence occurs in the sibling species C. suwai, while two inversions in C. plumosus can be derived from it through simple inversions. They regarded independent emergence of the same complex inversion in three species as unlikely and presented the common-ancestor interpretation as an inference.

Alongside inversions, the researchers recorded five translocation cases: two involving whole chromosome arms, one with breakpoints inside arms D and E, and a unique larva carrying two reciprocal whole-arm translocations. Rare variation in centromeric heterochromatin size was observed mainly in chromosome II in Western Siberia. B chromosomes occurred in some populations at frequencies of up to 30%.

They commonly lay near or contacted the centromeric heterochromatin of arm G, although the investigators could not determine whether some apparently isolated positions resulted from mechanical disruption of contacts during slide preparation. These observations describe chromosome structure and occurrence frequencies; they do not establish effects on fitness or development. Seven cytogenetic population types were identified.

Populations from Europe, the Urals and Eastern Siberia belonged to type 0, in which all main banding sequences were dominant. Most Western Siberian populations were type G, while others were assigned to types DG, FG and DFG. Far Eastern populations had types ADG and F.

Overall, the sampled Western Siberian populations showed higher chromosomal polymorphism and more varied cytogenetic structures than populations from Europe, Eastern Siberia or the Far East. The authors proposed that alternative sequences in arms D, F and G may have adaptive value in Western Siberia, but this was a hypothesis rather than a tested causal result. Cytogenetic distances among populations ranged from 0.001 to 0.461, with an average of 0.155 ± 0.024.

These within-species values were below the reported average interspecific distance of 2.618 ± 0.400 for seven species in the Chironomus plumosus group. A neighbour-joining analysis broadly grouped populations with similar cytogenetic structures but also placed some geographically distant populations together. The authors noted that water and detritus characteristics may influence chironomid population structure more directly than geography alone, although those environmental variables were not measured in this study.

Based on the greater inversion diversity, higher polymorphism and more varied population structures in Western Siberia, the authors proposed that the region may be the centre of the species’ range and possibly its place of origin; historical ancestry was not directly reconstructed.

Subject of Research: Chromosomal polymorphism across 41 populations of the midge Chironomus borokensis

Article Title: Chromosomal polymorphism in natural populations of Chironomus borokensis Kerkis, Filippova, Shobanov, Gunderina et Kiknadze, 1988 ( Diptera , Chironomidae )

Article References: Golygina, V. V., Broshkov, A. D., & Ermolaeva, O. V. (2025). Chromosomal polymorphism in natural populations of Chironomus borokensis Kerkis, Filippova, Shobanov, Gunderina et Kiknadze, 1988 (Diptera, Chironomidae). Comparative Cytogenetics, 19, 51-74. https://doi.org/10.3897/compcytogen.19.141735

Image Credits: AI Generated

DOI: 10.3897/compcytogen.19.141735

Keywords: Chironomus borokensis, chromosomal polymorphism, polytene chromosomes, inversions, translocations, B chromosomes, cytogenetic distance, Western Siberia, population genetics, Chironomus plumosus group, Chromosomal, polymorphism

The study included 120 patients with bladder cancer and 120 healthy controls matched by age and sex. Investigators genotyped the rs833061 variant using ARMS-PCR and confirmed the genotypes by Sanger sequencing. Serum YKL-40 concentrations were measured with ELISA.

Multivariable binary logistic regression showed that the CT and TT genotypes remained independently associated with increased bladder cancer susceptibility after adjustment for age, sex, and smoking status. Patients had significantly higher serum YKL-40 concentrations than controls, and those concentrations increased progressively with tumor stage. TT genotype carriers had the highest serum YKL-40 levels.

These observations connect a measured genetic variant with two related clinical features in the study population: bladder cancer status and circulating YKL-40. The source available for this report is the article abstract rather than a full assessment of the complete study. The authors characterized the genotype–phenotype relationship as preliminary and stated that the results require validation in larger multicentre cohorts.

Subject of Research: Association of VEGFA rs833061 polymorphism with bladder cancer susceptibility and serum YKL-40 concentrations in a case-control study

Article Title: Integrated analysis of VEGFA rs833061 (− 460T > C) promoter polymorphism and serum YKL-40 levels in bladder cancer: evidence of a genotype–phenotype association

Article References: Kaushik, R., Pawar, D., Sharma, A., Siwach, K., Rohilla, G., Narwal, S., Khatri, N., Arora, A., & Vashist, M. (2026). Integrated analysis of VEGFA rs833061 (− 460T > C) promoter polymorphism and serum YKL-40 levels in bladder cancer: evidence of a genotype–phenotype association. Molecular Biology Reports, 53(1), Article 1585. https://doi.org/10.1007/s11033-026-12776-w

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12776-w

Keywords: bladder cancer, VEGFA, rs833061, YKL-40, genetic polymorphism, case-control study, serum biomarker, genotype-phenotype association, Integrated, analysis, promoter, polymorphism

The mixed-suspension mixed-product-removal crystallizer has long served as the conceptual and practical workhorse of continuous crystallization. In an MSMPR vessel, the slurry is assumed to be well mixed, so that crystals of every size experience the same supersaturation environment, and the product stream withdrawn from the vessel has the same composition as the well-mixed contents. This idealization yields a particularly elegant theoretical consequence: the steady-state crystal population density distribution, when plotted on a logarithmic scale against particle size, becomes a straight line whose slope is directly related to the ratio of growth rate to residence time. This relationship has allowed generations of crystallization researchers to extract nucleation and growth kinetics directly from steady-state particle-size measurements, and it underpins the population-balance modeling framework used in the present study. At the same time, the well-mixed assumption introduces the very limitation that staging seeks to address, because a broad residence-time distribution means some crystals spend far longer in the vessel than others, and back-mixing can carry fine particles into environments where they continue to compete for supersaturation.

The tension at the heart of single-stage operation deserves elaboration. Supersaturation, the thermodynamic driving force for crystallization, must be generated somewhere in the process, whether by cooling, antisolvent addition, or evaporation. In a single vessel, that driving force is spent on competing processes: nucleation of new crystals, growth of existing ones, and, in polymorphic systems, the selection and maintenance of the desired solid form. High supersaturation favors nucleation, which multiplies the crystal population and divides the available solute among more particles, yielding smaller crystals with wider distributions. Low supersaturation favors growth on existing crystal surfaces, which produces larger and more uniform particles but leaves more solute unconverted and reduces the productivity of the equipment. These are not merely engineering inconveniences; they reflect the fundamental kinetics of how crystals are born and how they grow, and no single set of operating conditions can optimize both simultaneously in one vessel.

Staging resolves this conflict by temporal separation rather than by compromise. In a two-stage configuration, the first vessel can operate at conditions that favor controlled nucleation and early growth, while the second vessel operates at lower supersaturation, where the crystal population that survived the first stage can grow to its target size without the disruptive generation of new nuclei. The comparison reported for paracetamol and carbamazepine is methodologically significant precisely because it holds total active volume and overall residence time constant between the single-stage and two-stage configurations. Without this constraint, any improvement observed in a staged system could simply be attributed to the additional equipment volume or longer processing time. By matching these variables, the study isolates the effect of how supersaturation is distributed in time and space, and the results make a clear argument: the benefit of staging lies in the controlled distribution of the driving force, not in added capacity.

The choice of model compounds strengthens the generality of these findings. Paracetamol crystallizing as Form I represents a relatively well-behaved cooling crystallization system, one that has become a standard benchmark in crystallization research because its solubility behavior, metastable-zone width, and growth kinetics have been extensively characterized. Carbamazepine crystallizing as Form III presents a more demanding challenge, because carbamazepine is notorious among pharmaceutical polymorphs for the complexity of its solid-form landscape, with multiple anhydrous and solvated forms that can interconvert depending on temperature, solvent composition, and mechanical history. Antisolvent-assisted cooling crystallization of carbamazepine must therefore manage not only particle size but also the risk of nucleating or transforming into an undesired polymorph. That the two-stage configuration improved polymorphic selectivity in both systems, despite their contrasting crystallization behavior, suggests that the underlying mechanism, namely the suppression of secondary nucleation through staged desupersaturation, operates across chemically distinct APIs.

The experimental design employed here reflects the maturing methodology of quality-by-design in pharmaceutical development. The Box-Behnken design is a response-surface approach that efficiently samples a four-factor experimental space with fewer runs than a full factorial design while avoiding the extreme corner combinations that might push the process into inoperable regimes. By applying independent designs to each compound, the study acknowledges that paracetamol and carbamazepine respond differently to the same process levers, and that a compound-specific operating space is more informative than a generic one. The four factors chosen, residence time, relative supersaturation, seed loading, and power input per unit volume, span the principal degrees of freedom available to a crystallization engineer. Seed loading deserves particular attention, because continuous crystallization differs fundamentally from batch operation in how seeding is implemented: rather than charging a single dose of seed crystals at the start, continuous operation requires a continuous stream of seed material, which raises practical questions about seed preparation, seed quality, and the long-term consistency of the seed supply.

The population-balance modeling component illustrates both the power and the requirements of mechanistic crystallization modeling. A population-balance equation describes how the number of crystals in each size class evolves over time under the combined influences of nucleation, growth, breakage, agglomeration, and removal. When calibrated against experimental data and, critically, validated against data not used in the fitting process, such models can interpolate within the experimental domain and support scenario analysis for operating conditions that were not directly tested. The reported coefficients of determination between 0.894 and 0.943, with normalized root-mean-square errors between 1.8 and 8.8 percent, indicate that the models captured the dominant behavior of both systems with useful quantitative fidelity. The emphasis on external validation is important, because crystallization models calibrated on one dataset can appear deceptively accurate while failing to generalize, particularly when kinetic parameters are correlated or when the model structure omits relevant phenomena such as breakage or size-dependent growth.

The multimodal process analytical technology deployed in the study reflects a broader trend toward real-time monitoring in continuous pharmaceutical manufacturing. Attenuated total reflection Fourier-transform infrared spectroscopy and Raman spectroscopy probe the liquid and solid phases respectively, allowing dissolved concentration and polymorphic content to be estimated without withdrawing samples. Focused-beam reflectance measurement provides chord-length distributions, which are related to but not identical with true particle-size distributions, since the measured chords depend on particle shape, orientation, and the concentration of the suspension. The careful validation of these online measurements against independent offline references, such as laser diffraction and microscopy, is what transforms them from trend indicators into quantitative process monitors. This validation work, though less glamorous than the optimization results themselves, is essential for regulatory acceptance of real-time release testing and for the closed-loop control strategies that continuous crystallization ultimately promises.

The attention paid to fouling and downstream processability distinguishes this work from much of the continuous-crystallization literature, which has historically prioritized yield and particle size. Fouling, the accumulation of crystal deposits on vessel walls, impellers, and heat-transfer surfaces, is a persistent operational challenge in continuous crystallizers. It degrades heat transfer, alters the effective working volume, disturbs mixing and residence-time distribution, can blind optical PAT probes, and eventually forces shutdown for cleaning, undermining the very continuity that justifies continuous operation. The finding that two-stage operation reduced fouling by roughly 42 to 46 percent for the two compounds is therefore operationally meaningful, and the mechanism is plausible: by lowering the supersaturation experienced in each individual vessel, staging reduces the thermodynamic driving force for heterogeneous nucleation on surfaces, which is a principal pathway for fouling formation.

The downstream consequences of particle attributes are equally concrete. Filtration time declined by 26.3 percent for paracetamol and 34.4 percent for carbamazepine when the two-stage configuration was used, a direct consequence of the larger median particle sizes and narrower distributions. The relationship between particle size and filtration follows from classical cake-filtration theory, in which the specific cake resistance varies inversely with particle size, so that modest increases in median size can produce disproportionate reductions in filtration time. Narrower distributions further improve washing efficiency and reduce mother-liquor retention, which affects both drying time and final product purity. Elongated or needle-like crystals, which often result from high-supersaturation conditions, pack poorly in filter cakes and create high resistance; the reported improvements in morphology under staged operation therefore compound the benefits of size alone.

The trade-off between product quality and space-time yield deserves honest acknowledgment. Longer residence times improved particle size, distribution width, and polymorphic content, but reduced space-time yield, meaning that a given equipment volume produced less material per unit time. This is not a flaw in the study but a genuine feature of crystallization physics: crystal growth takes time, and time spent growing is time during which the vessel is not processing new feed. The practical resolution of this trade-off depends on which constraints dominate a given manufacturing scenario, whether the bottleneck is downstream filtration capacity, equipment volume, or product quality specifications. The value of the response-surface models developed here is precisely that they allow such trade-offs to be quantified and navigated rather than discovered by trial and error.

The preservation of chemical purity and mass-balance closure across all configurations provides an important baseline assurance. Mass-balance closure, the accounting identity that solute entering the system must equal solute leaving in product and mother liquor, is a stringent test of experimental rigor in continuous operation, because it requires accurate measurement of flows, concentrations, and solids contents over extended steady-state periods. That closure was maintained while fouling was present in the single-stage configuration suggests careful experimental technique, and it lends credibility to the comparative conclusions. Similarly, the extended polymorphic stability testing addresses a concern specific to continuous operation: because continuous crystallizers operate at steady state for long periods, any slow polymorphic transformation that would be invisible in a batch process could accumulate over time and compromise the solid form of the product.

Looking beyond the two compounds studied, the findings suggest a design principle for continuous pharmaceutical crystallization that is likely to generalize: the distribution of supersaturation across stages is a primary design variable, comparable in importance to residence time or temperature profile. The authors are appropriately measured in their claims, presenting the work as a reproducible demonstration for two APIs with contrasting behavior rather than a universal framework. Extending the approach to compounds with different solubility temperature-dependence, different growth kinetics, or different polymorphic landscapes would test the boundaries of the principle, as would configurations with more than two stages or with interstage seeding or fines dissolution. The combination of structured experimentation, externally validated mechanistic modeling, multimodal PAT, and operational metrics such as fouling and filtration time offers a template for how continuous crystallization research can connect molecular-level phenomena to manufacturing-relevant outcomes, and it is this end-to-end perspective that gives the study its practical significance for the pharmaceutical industry’s ongoing transition toward continuous manufacturing.

Subject of Research: Continuous crystallization of pharmaceutical compounds in mixed suspension mixed product removal systems

Article Title: Continuous crystallization of pharmaceutical compounds in mixed suspension mixed product removal systems

Article References: Tan, F. (2026). Continuous crystallization of pharmaceutical compounds in mixed suspension mixed product removal systems. Frontiers in Chemistry, 14, Article 1947756. https://doi.org/10.3389/fchem.2026.1947756

Image Credits: AI Generated

DOI: 10.3389/fchem.2026.1947756

Keywords: continuous crystallization, MSMPR, pharmaceutical manufacturing, paracetamol, carbamazepine, polymorphism, population-balance modeling, process analytical technology, particle-size distribution, fouling, filtration, quality by design

The timing of the call reflects a growing crisis in drug development that has little to do with discovering new molecules and everything to do with delivering them. An estimated large fraction of newly discovered drug candidates, particularly those emerging from high-throughput screening campaigns, are classified as poorly water-soluble. These compounds may bind their biological targets beautifully in vitro yet fail to reach therapeutic concentrations in the bloodstream because they simply cannot dissolve in gastrointestinal fluids. Particle engineering has emerged as the discipline that confronts this problem head-on, manipulating the size, shape, morphology, and solid-state form of drug particles to maximize the surface area available for dissolution and to stabilize thermodynamically unfavorable but therapeutically useful states.

Among the most influential techniques in this field is micronization, which reduces particle size into the low-micrometer range, and its more extreme descendant, nanonization, which pushes particles below one micrometer and often below 100 nanometers. At these scales, according to the Noyes-Whitney equation that governs dissolution kinetics, the rate at which a particle dissolves is directly proportional to its surface area, so shrinking particles dramatically accelerates the release of drug into solution. Nanocrystal suspensions stabilized by surfactants or polymeric stabilizers have already reached the market in several oral and injectable products, demonstrating that particle-scale manipulation can translate into clinically meaningful improvements in bioavailability. The special issue explicitly invites contributions on such particle engineering approaches for solubility, stability, and bioavailability enhancement, signaling that the editors want the full breadth of current methodology represented.

Equally central to the call is solid-state science, the study of how drug molecules arrange themselves in the solid phase. A single active pharmaceutical ingredient can exist in multiple crystalline polymorphs, each with a distinct lattice energy and therefore a distinct solubility, melting point, and physical stability profile. It can also be rendered amorphous, lacking any long-range crystalline order, which confers a substantial solubility advantage but introduces the persistent risk of recrystallization during storage. The infamous case of ritonavir, an HIV protease inhibitor whose market launch was derailed in the late 1990s when a previously unknown, more stable and far less soluble polymorph spontaneously appeared in production, remains the canonical warning of what happens when solid-state behavior is incompletely mapped. Modern developers now deploy a battery of characterization tools, including powder X-ray diffraction, differential scanning calorimetry, dynamic vapor sorption, and solid-state nuclear magnetic resonance, to detect and control these forms, and the special issue places solid-state characterization and control squarely among its priority topics.

Beyond solubility, the call for papers reaches across the entire landscape of dosage forms and delivery routes. The editors list advanced formulation strategies for oral, injectable, inhalable, and transdermal products, alongside broader advanced drug delivery systems. Each route imposes its own demanding constraints. Oral formulations must survive gastric acid, digestive enzymes, and the variable pH of the intestinal tract before releasing their payload at the right site and rate. Inhaled products must generate aerosol droplets or dry powder particles in a narrow aerodynamic size band, typically one to five micrometers, so that they deposit in the deep lung rather than being exhaled or trapped in the throat. Transdermal systems must drive molecules across the skin’s stratum corneum, a barrier that admits very few drugs, often requiring chemical permeation enhancers, microneedle arrays, or engineered vesicles. Injectable formulations face the strictest requirements of all, demanding sterility, isotonicity, appropriate viscosity, and freedom from particulate contamination. Formulation science is the discipline that reconciles a molecule’s intrinsic chemistry with these route-specific physiological realities.

A distinctive emphasis of this special issue is translational formulation science and the scale-up of drug products, the often underappreciated passage from a well-behaved bench process to a robust manufacturing operation producing hundreds of thousands of units. Processes that work flawlessly in a one-kilogram laboratory batch can behave entirely differently at industrial scale. Spray drying, hot-melt extrusion, high-shear wet granulation, and fluid-bed coating all involve heat and mass transfer phenomena whose balance shifts with equipment geometry, batch size, and processing time. A spray-dried amorphous dispersion, for example, depends on rapid solvent evaporation to lock the drug in its amorphous state; slower drying at scale can allow phase separation or crystallization that destroys the solubility advantage the technology was chosen to deliver. Translational research that documents how formulation critical quality attributes survive, or fail to survive, the journey to commercial scale is precisely what the editors hope to attract.

Running through the topic list is a pair of acronyms that have reshaped pharmaceutical manufacturing culture over the past two decades: QbD and PAT. Quality by Design is a regulatory philosophy, championed by agencies including the US Food and Drug Administration, that holds that quality should be built into a product by design rather than tested in at the end of the line. In practice, developers identify critical quality attributes of the drug product, determine which raw material properties and process parameters influence them, and establish a design space within which the process can operate while consistently delivering acceptable quality. Process Analytical Technology supplies the real-time sensory apparatus for this vision, using tools such as near-infrared spectroscopy, Raman spectroscopy, and focused beam reflectance measurement to monitor blend uniformity, granule moisture, particle size distribution, and polymorphic form during production rather than after it. Contributions applying QbD and PAT to formulation and manufacturing are explicitly solicited, reflecting how thoroughly these frameworks now permeate both industrial practice and regulatory expectation.

The special issue also embraces emerging manufacturing technologies in dosage form design and commercial production, a category that encompasses some of the most dynamic developments in the field. Additive manufacturing, best known in the form of three-dimensional printing, has already produced the first FDA-approved printed drug product, an orally disintegrating levetiracetam tablet whose highly porous internal architecture enables rapid disintegration. Continuous manufacturing, which replaces the traditional batch-and-warehouse model with a steady flow of material through integrated unit operations, promises shorter production times, smaller footprints, and tighter process control, and has gained regulatory acceptance in several recent drug product approvals. Other frontiers include microfluidic production of lipid nanoparticles, the delivery platform underpinning mRNA vaccines, and precision coating technologies that enable functional film layers measured in micrometers. Researchers working on such technologies will find their subject matter directly addressed in the call for papers.

For the pharmaceutical research community, the significance of the issue lies in its insistence on the word translational. The history of drug delivery is littered with elegant laboratory concepts, from targeted nanoparticles to stimuli-responsive polymers, that never survived contact with manufacturing economics, regulatory scrutiny, or patient practicality. By framing the issue around particle engineering and formulation science as the engines of dosage form development, the guest editors are drawing attention to the disciplines that decide whether a molecule becomes a medicine. The Journal of Pharmaceutical Investigation, published by Springer, has long served as a venue for research spanning pharmaceutics, drug delivery, and pharmaceutical technology, particularly with strong participation from Asian research groups and industry laboratories, and the January 2027 issue is positioned to consolidate that role.

Researchers wishing to contribute have until June 30, 2026, to submit their manuscripts, with the completed issue slated for January 2027. Correspondence regarding the issue is directed to the three guest editors at their respective institutions. For scientists working at the intersection of particle engineering, solid-state chemistry, formulation design, and manufacturing technology, the call represents a focused opportunity to place their work within a collection explicitly dedicated to the path from molecular promise to manufactured product. In an era when biological targets are discovered faster than they can be drugged, and when a growing share of the pharmacopoeia consists of molecules that resist dissolution, the sciences gathered under this special issue’s banner may well determine how much of modern drug discovery ever reaches a patient.

Subject of Research: Translational pharmaceutical dosage form development based on particle engineering and formulation science

Article Title: Special Issue: Translational Advances in Pharmaceutical Dosage Form Development Based on Particle Engineering and Formulation Science

Article References: Special Issue: Translational Advances in Pharmaceutical Dosage Form Development Based on Particle Engineering and Formulation Science. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: particle engineering, formulation science, drug delivery, solubility enhancement, solid-state characterization, polymorphism, amorphous dispersions, Quality by Design, Process Analytical Technology, continuous manufacturing, scale-up, bioavailability

At first glance, a call for papers might seem like an administrative event, but in pharmaceutical science these themed collections often signal where the field believes its bottlenecks lie. The topics listed by the editors span the entire journey of a medicine, from the first manipulation of a molecule’s solid form to the validated, regulated manufacturing line that produces billions of tablets or inhaler canisters. That journey is where many promising drug candidates historically have stalled, and it is precisely the territory this special issue aims to cover.

The first listed topic, particle engineering approaches for solubility, stability, and bioavailability enhancement, addresses one of the most persistent problems in modern pharmacology. A large proportion of newly discovered drug molecules are poorly soluble in water, which means they dissolve slowly or incompletely in the gastrointestinal tract and never reach the bloodstream at therapeutic levels. Particle engineering attacks this problem by changing the physical characteristics of the drug particles themselves, reducing them to micron or nanometer dimensions to dramatically increase the surface area available for dissolution, or converting them into amorphous forms that carry higher free energy and therefore dissolve more readily than their stable crystalline counterparts.

These interventions come with trade-offs that make the field technically demanding. Nanocrystals stabilized by surfactants or polymers can aggregate during storage, undoing the dissolution advantage they were designed to provide. Amorphous solid dispersions, in which a drug is molecularly dispersed in a glassy polymer carrier, risk reverting to the crystalline state over time, a process known as recrystallization that can silently destroy bioavailability. The special issue’s emphasis on stability alongside solubility reflects this reality: a formulation that works on the day it is made but fails on the shelf is not a medicine. Researchers in this area increasingly combine experimental screening with computational prediction of molecular interactions to select carriers and processing conditions that lock in the desired physical state for the product’s entire lifetime.

The second topic broadens the view to advanced formulation strategies across every major route of administration, including oral, injectable, inhalable, and transdermal dosage forms, as well as advanced drug delivery systems. Each route imposes its own engineering constraints. Oral products must survive stomach acid and enzymatic attack before releasing their payload in the intestine. Injectable formulations must be sterile, isotonic, and free of particles that could trigger immune reactions. Inhaled medicines demand particles engineered to an aerodynamic diameter typically in the range of one to five micrometers so they can navigate the branching airways and deposit deep in the lungs rather than being exhaled or trapped in the throat. Transdermal systems must push molecules through the skin’s stratum corneum, a barrier that admits very few drugs without chemical enhancers, iontophoresis, or microneedle arrays.

The inclusion of advanced drug delivery systems in the scope signals interest in platforms that go beyond conventional pills and syringes: long-acting injectable depots that release drug over weeks or months, lipid nanoparticles that carry messenger RNA into cells, and targeted carriers designed to accumulate in diseased tissue. The lipid nanoparticle field in particular demonstrated its translational maturity during the COVID-19 pandemic, when the same core technology that had been refined for decades in nucleic acid delivery underpinned the first authorized mRNA vaccines. Formulation science, once viewed as a downstream service to drug discovery, has become a discipline capable of enabling entirely new therapeutic modalities.

Solid-state characterization and control, the third topic, is the analytical backbone supporting everything else. A single drug substance can exist in multiple crystalline forms, called polymorphs, each with different solubility, melting point, mechanical behavior, and stability. The classic cautionary tale is ritonavir, an HIV drug that in the late 1990s began crystallizing in a previously unknown, far less soluble polymorph during manufacturing, forcing a market withdrawal while the problem was solved. Modern development therefore relies on a battery of techniques, including X-ray powder diffraction to identify crystal structures, differential scanning calorimetry to map thermal transitions, dynamic vapor sorption to probe hygroscopicity, and spectroscopic methods such as Raman and near-infrared analysis to track molecular-level changes. Controlling the solid state means controlling which form appears during crystallization, which form survives drying and milling, and which form remains stable through years of storage in humid warehouses and medicine cabinets.

The fourth and fifth topics, translational formulation science with scale-up, and emerging manufacturing technologies, tackle the gap between what works in a laboratory beaker and what can be produced reliably at commercial scale. A formulation optimized in gram quantities may behave entirely differently when processed in hundreds of kilograms, because mixing efficiency, heat transfer, and residence time distributions all change with equipment size. Continuous manufacturing, in which product flows through connected unit operations rather than being made in discrete batches, has gained regulatory acceptance and offers tighter control, smaller facility footprints, and faster response to demand. Hot-melt extrusion, which continuously converts drug and polymer into amorphous solid dispersions by kneading them at elevated temperature, and spray drying, which rapidly fixes amorphous particles from a solution, are established examples of technologies that moved from niche to mainstream. Additive manufacturing, including 3D printing of tablets with tailored internal geometries that control release kinetics, represents the emerging frontier.

The final topic, applications of Quality by Design and Process Analytical Technology, describes the regulatory and quality philosophy that binds the whole enterprise together. Quality by Design, or QbD, asks developers to understand which formulation variables and process parameters critically affect product quality, and to design a design space within which those factors can vary while the product still meets its specifications. Process Analytical Technology, or PAT, supplies the real-time measurement tools, such as inline near-infrared spectroscopy and Raman probes, that make such control possible during production rather than through end-of-batch testing alone. Together they shift quality from being inspected into a product to being built into it, a change regulators have promoted for two decades and one that continuous manufacturing makes genuinely practical.

What makes this special issue notable is its explicitly translational framing. The phrase signals that the editors want work that bridges disciplines and moves toward patients, not isolated laboratory observations. For a journal based in Asia with an international authorship, the collection also highlights the region’s growing weight in pharmaceutical development, with guest editors drawn from three Korean universities active in drug delivery research. As poorly soluble molecules, biologics, and nucleic acid therapeutics continue to dominate development pipelines, the engineering of particles and formulations is likely to determine which laboratory discoveries ever become medicines. Submissions are open until June 30, 2026, and the resulting issue, due in January 2027, will offer a snapshot of a field working to make the next generation of drugs deliverable.

Subject of Research: Translational pharmaceutical dosage form development based on particle engineering and formulation science

Article Title: Special Issue: Translational Advances in Pharmaceutical Dosage Form Development Based on Particle Engineering and Formulation Science

Article References: Special Issue: Translational Advances in Pharmaceutical Dosage Form Development Based on Particle Engineering and Formulation Science. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: particle engineering, formulation science, drug delivery, bioavailability, solid-state characterization, amorphous solid dispersions, Quality by Design, Process Analytical Technology, continuous manufacturing, pharmaceutical scale-up, polymorphism, Journal of Pharmaceutical Investigation

The premise behind the issue is deceptively simple: a drug molecule is only as useful as the dosage form that delivers it. Many of the most promising compounds emerging from discovery pipelines today are poorly soluble in water, chemically fragile, or difficult to absorb through biological membranes. Particle engineering addresses these problems at the physical level, manipulating crystal form, particle size, surface properties, and morphology to change how a drug dissolves, remains stable on the shelf, and ultimately reaches the bloodstream. The special issue explicitly invites contributions on particle engineering approaches for solubility, stability, and bioavailability enhancement, signaling that the editors see this as the foundational layer upon which modern dosage form design is built.

The scientific stakes are considerable. Estimates across the pharmaceutical literature consistently suggest that a large fraction of new chemical entities, and an even larger share of compounds emerging from high-throughput screening, fall into the Biopharmaceutics Classification System classes II and IV, meaning their absorption is limited by poor aqueous solubility. Techniques such as micronization, nanocrystal formation, amorphous solid dispersion, hot-melt extrusion, spray drying, and supercritical fluid processing have each been developed to confront this barrier. Each method reshapes the solid state of the drug in a different way: reducing particle size to increase surface area, disrupting crystal lattices to raise apparent solubility, or stabilizing metastable polymorphs that dissolve faster than their thermodynamically favored counterparts. The catch, and a recurring theme in translational formulation science, is that these engineered states are often physically unstable, prone to recrystallization, aggregation, or phase conversion during storage and processing.

This is where solid-state characterization enters the picture. The special issue calls for work on solid-state characterization and control in pharmaceutical development, a discipline that combines X-ray powder diffraction, differential scanning calorimetry, dynamic vapor sorption, spectroscopic methods, and increasingly sophisticated computational modeling to understand exactly what form a drug is in and how that form behaves. Polymorphism, the ability of a single molecule to crystallize in multiple distinct lattice arrangements, remains one of the most consequential and litigated phenomena in the industry, because different polymorphs can exhibit different solubility, dissolution rates, mechanical properties, and stability profiles. Controlling the solid state is therefore not an academic nicety; it determines whether a product can be manufactured reproducibly, whether it survives humidity and temperature stress, and whether regulators will approve it.

Beyond the solid state, the issue’s scope extends to advanced formulation strategies across essentially every route of administration: oral, injectable, inhalable, transdermal, and other delivery systems. Each route imposes its own engineering constraints. Oral formulations must survive gastric acid and enzymatic attack before releasing their payload in the intestine. Injectable products demand strict control of sterility, particle contamination, and osmolality, and increasingly rely on lipid nanoparticles and polymeric carriers for biologics and nucleic acid therapeutics. Inhaled medicines require particles engineered to aerodynamic diameters typically in the range of one to five micrometers so they can deposit in the deep lung rather than being exhaled or trapped in the throat. Transdermal systems must push molecules across the stratum corneum, the skin’s remarkably effective barrier, using chemical enhancers, microneedles, or iontophoresis. The fact that a single issue can span all of these routes reflects how particle and formulation science has become a unifying language across delivery technologies.

Perhaps the most distinctive emphasis of the special issue, and the one captured in its title, is translation. The editors are asking for work on translational formulation science and scale-up of drug products, which addresses a notorious weak point in pharmaceutical research. A formulation that performs beautifully in a one-liter beaker may fail spectacularly when produced in a two-thousand-liter vessel, where mixing times, heat transfer, drying kinetics, and shear forces all change. Scale-up failures can alter particle size distributions, polymorphic content, and blend uniformity in ways that compromise both efficacy and regulatory compliance. Translational formulation science seeks to anticipate these shifts through mechanistic process models, material science characterization of excipients and active ingredients, and careful design of experiments that map how process variables propagate into product quality.

Emerging manufacturing technologies form another pillar of the call for papers. Continuous manufacturing, in which raw materials flow through an integrated train of unit operations rather than moving between batch steps, has gained regulatory momentum because it offers tighter process control, smaller footprints, and the ability to adjust production volume rapidly. Additive manufacturing, commonly known as three-dimensional printing, has opened the possibility of dosage forms with complex internal geometries and, in principle, patient-specific dosing. Electrospinning, microfluidics, and advanced spray-based techniques are being explored to produce engineered particles with architectures that conventional milling and crystallization cannot achieve. The special issue’s invitation for contributions on emerging manufacturing technologies in dosage form design and commercial production suggests the editors want to see not just novel laboratory demonstrations but evidence that these approaches can survive contact with commercial reality.

Woven through all of these topics is the regulatory and analytical framework of Quality by Design and Process Analytical Technology. Quality by Design, or QbD, inverts the traditional approach to pharmaceutical development: instead of testing finished products and rejecting failures, developers build a scientific understanding of how formulation and process variables affect critical quality attributes, then design the product and process to stay within a proven region of acceptable performance. Process Analytical Technology, or PAT, supplies the real-time eyes for this philosophy, using inline and online sensors such as near-infrared spectroscopy, Raman spectroscopy, and focused beam reflectance measurement to monitor blend uniformity, granulation endpoints, drying progress, and crystallization as they happen. Together, QbD and PAT shift quality from an inspection outcome to an engineered property, and both regulators and manufacturers have invested heavily in their adoption. The special issue’s explicit call for QbD and PAT applications in formulation and manufacturing underscores that computational and analytical rigor is now inseparable from dosage form innovation.

The timing of the issue, arriving in early 2027, positions it to capture a field in rapid flux. The rise of biologics, mRNA therapeutics, and antibody-drug conjugates has expanded the formulation scientist’s brief far beyond small-molecule tablets, demanding new excipient systems, cold-chain-compatible lyophilization cycles, and delivery vehicles that protect fragile macromolecules. At the same time, artificial intelligence and machine learning are beginning to influence formulation development, from predicting polymorph stability to optimizing process parameters, adding a computational layer to what has historically been an empirical discipline. Researchers working at any of these intersections, whether in academia, generic and innovator pharmaceutical companies, or contract development and manufacturing organizations, now have a defined venue and deadline: submissions are due by June 30, 2026, for an issue that promises to map how particle engineering and formulation science carry new medicines from the bench to the pharmacy shelf.

For patients, the significance of this largely invisible branch of pharmaceutical science is difficult to overstate. A breakthrough molecule that cannot be dissolved, stabilized, or manufactured at scale is, in practical terms, not a medicine at all. The disciplines gathered under this special issue, spanning particle engineering, solid-state control, advanced delivery systems, translational scale-up, emerging manufacturing, and quality-by-design frameworks, collectively determine whether the drugs of the next decade arrive as effective, affordable, and reliable products. By convening international contributions under a single translational banner, the Journal of Pharmaceutical Investigation and its guest editors are betting that the next wave of therapeutic progress will depend as much on the engineering of particles and processes as on the discovery of the molecules themselves.

Subject of Research: Translational pharmaceutical dosage form development based on particle engineering and formulation science

Article Title: Special Issue: Translational Advances in Pharmaceutical Dosage Form Development Based on Particle Engineering and Formulation Science

Article References: Special Issue: Translational Advances in Pharmaceutical Dosage Form Development Based on Particle Engineering and Formulation Science. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: particle engineering, formulation science, drug delivery, bioavailability, solid-state characterization, polymorphism, scale-up, continuous manufacturing, Quality by Design, Process Analytical Technology, pharmaceutical manufacturing, dosage forms

The timing could hardly be better. An estimated large fraction of drug candidates emerging from discovery pipelines today are poorly soluble in water, a property that can doom a promising molecule before it ever reaches patients. When a compound dissolves too slowly or too incompletely in the gastrointestinal tract, the body absorbs too little of it, forcing higher doses, more frequent administration, or outright abandonment of the candidate. Particle engineering attacks this problem at its physical root. By reducing particle size into the micrometer and nanometer ranges, formulators dramatically increase the surface area available for dissolution, following the well-established Noyes-Whitney relationship that links dissolution rate to exposed surface area. Nanocrystal suspensions, produced by wet milling, high-pressure homogenization, or controlled precipitation, have already carried several blockbusters onto the market, and the techniques continue to evolve toward finer control of size distributions and surface properties.

But size is only one lever. The special issue’s first listed topic, particle engineering approaches for solubility, stability, and bioavailability enhancement, encompasses a family of strategies that manipulate the solid state of a drug itself. Many poorly soluble compounds exist in crystalline forms whose tightly packed lattices resist interaction with water. Converting a drug to an amorphous solid, in which molecules are arranged randomly as in a glass rather than in an ordered crystal, can raise apparent solubility by several-fold. The catch is stability: amorphous materials have a thermodynamic drive to recrystallize, which would erase the solubility advantage and potentially alter the product’s performance over its shelf life. Formulators fight back with glass solutions, in which the drug is molecularly dispersed in a polymer carrier and stabilized by intermolecular interactions, and with co-amorphous systems pairing the drug with a second small molecule. Hot-melt extrusion, spray drying, and more recently electrospinning and cryomilling are among the manufacturing routes used to generate these metastable phases reproducibly.

Polymorphism, the ability of a single molecule to crystallize in multiple distinct forms, adds another layer of complexity that the special issue explicitly targets through its topic on solid-state characterization and control. Different polymorphs can differ in melting point, dissolution rate, mechanical properties, and chemical stability, and regulatory agencies require manufacturers to identify and control the form used in a product. The most infamous cautionary tale remains ritonavir, an HIV drug whose second, more stable polymorph surfaced unexpectedly in the late 1990s and effectively halted production until the problem was solved. Modern analytical arsenic, so to speak, includes powder X-ray diffraction, differential scanning calorimetry, dynamic vapor sorption, solid-state nuclear magnetic resonance, and Raman spectroscopy, often deployed in combination to build a complete picture of a material’s solid-state landscape. Computational crystal structure prediction is increasingly used alongside these tools to assess whether undiscovered, potentially problematic forms might lurk beyond those found experimentally.

The second pillar of the call for papers, advanced formulation strategies for pharmaceutical dosage forms and drug delivery systems, stretches across every route of administration. Oral solid dosage forms remain the workhorse of the pharmaceutical industry, prized for patient convenience and manufacturing economy, and innovation there includes modified-release architectures that choreograph drug release over hours, gastroretentive systems that extend residence time in the stomach, and fixed-dose combinations that pack multiple actives into a single tablet. Injectable formulations demand entirely different constraints: sterility, isotonicity, acceptable viscosity for syringeability, and control of protein aggregation for the growing class of biologic drugs. Inhalable products must balance aerodynamic particle size, typically targeting the one-to-five-micrometer range for deep lung deposition, with the device engineering needed to disperse powder consistently with each breath. Transdermal systems, from matrix patches to microneedle arrays that painlessly breach the stratum corneum, promise needle-free delivery of molecules that would otherwise be destroyed by first-pass metabolism in the liver.

What unites these diverse routes is the translational question that gives the special issue its name: how do laboratory-scale innovations become robust commercial products? A formulation that performs beautifully in a beaker can fail spectacularly when scaled to hundreds of kilograms. Mixing times, heat transfer, drying kinetics, and compaction behavior all change with scale, and subtle shifts in process conditions can convert a desired polymorph into an unwanted one or push an amorphous system past its crystallization threshold. The special issue’s topic on translational formulation science and scale-up of drug products invites contributions that document these journeys, including the analytical bridging studies that demonstrate a scaled process delivers the same product as the original. Case studies of technology transfer, particularly for enabling technologies like nanocrystals and amorphous solid dispersions, are exactly the kind of practical knowledge the field’s literature has historically under-supplied.

Emerging manufacturing technologies form another headline topic. Continuous manufacturing, in which raw materials flow through an integrated train of unit operations rather than sitting in batch vessels, is reshaping how small-molecule drugs are produced. Hot-melt extrusion is inherently continuous, and continuous blending, granulation, and tableting lines now operate under regulatory approvals in several markets. The appeal is twofold: smaller footprints and inventories, and tighter, real-time control of product attributes. Additive manufacturing has entered the conversation as well, with printing technologies capable of producing tablets with complex internal geometries and personalized doses, an approach validated by the first regulatory approval of a printed medicine. For biologics, advances in aseptic processing, including closed-system filling and isolator technology, are reducing contamination risk while enabling the high-concentration formulations that patients increasingly prefer in lower-volume injections.

Woven through all of these topics is the quality framework that regulators and industry have converged on over the past two decades: Quality by Design, or QbD, and its operational partner, Process Analytical Technology, or PAT. QbD inverts the traditional approach to pharmaceutical quality. Rather than testing finished products and rejecting failures, manufacturers first define the quality target product profile, identify the critical quality attributes that determine safety and efficacy, and map the critical material attributes and process parameters that control them. The result is a design space, a multidimensional region of operating conditions within which quality is assured by design, giving manufacturers regulatory flexibility to adjust processes without prior approval. PAT supplies the sensory apparatus: near-infrared and Raman spectroscopy probes embedded in process streams, inline particle size analyzers, and mass spectrometry interfaces that feed continuous data into control systems. Together they enable real-time release testing, in which product quality is confirmed during manufacture rather than days later in a quality-control laboratory.

The guest editors’ institutional affiliations reflect the strength of Korean pharmaceutical formulation science on the global stage. Sung-Joo Hwang at Yonsei University has a long record in drug delivery and formulation development, Min-Soo Kim at Pusan National University works extensively on particle engineering and solubility enhancement, and Heejun Park at Duksung Women’s University contributes expertise in pharmaceutical formulation and physical pharmacy. Their stewardship signals that the issue will emphasize both fundamental rigor and industrial relevance, a combination the Journal of Pharmaceutical Investigation has cultivated as a bridge between academic discovery and commercial practice in Asia and beyond.

For researchers, the June 30, 2026 deadline leaves roughly a year and a half to prepare contributions, and the scope is broad enough to welcome work ranging from molecular-level solid-state studies to full-scale manufacturing case reports. For the industry and the patients it serves, the stakes are concrete. Every improvement in solubility enhancement can rescue a drug candidate that would otherwise be shelved; every advance in continuous manufacturing and PAT can shorten the path from plant to pharmacy and reduce the risk of recalls rooted in solid-state surprises; and every refinement in delivery technology can make medicines easier to take, more comfortable to receive, and more effective once inside the body. The special issue arrives at a moment when the pharmaceutical sciences are increasingly recognized not as a downstream service to drug discovery but as a decisive discipline in its own right, one that determines whether the molecules of tomorrow ever become the medicines of today. Submissions and editorial correspondence are directed to the three guest editors through the journal, and the published collection is expected in January 2027.

Subject of Research: Translational pharmaceutical dosage form development using particle engineering and formulation science

Article Title: Special Issue: Translational Advances in Pharmaceutical Dosage Form Development Based on Particle Engineering and Formulation Science

Article References: Special Issue: Translational Advances in Pharmaceutical Dosage Form Development Based on Particle Engineering and Formulation Science. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: particle engineering, formulation science, drug delivery, solubility enhancement, bioavailability, solid-state characterization, polymorphism, amorphous solid dispersions, Quality by Design, Process Analytical Technology, continuous manufacturing, Journal of Pharmaceutical Investigation

The central challenge the special issue addresses is deceptively simple to state and extraordinarily difficult to solve. An estimated large fraction of newly discovered drug candidates, particularly the small molecules emerging from high-throughput screening campaigns, are poorly soluble in water. A molecule may bind its biological target with exquisite precision in a test tube, yet if it cannot dissolve in the fluids of the gastrointestinal tract or in the bloodstream, it will never reach therapeutic concentrations in the body. This is where particle engineering enters the picture. By manipulating the size, shape, crystal form, and surface properties of drug particles down to the nanometer scale, scientists can dramatically alter how a compound dissolves, how stable it remains on the shelf, and how much of it ultimately becomes available to the body, a property known as bioavailability.

The guest editors steering the issue bring complementary expertise to this agenda. Sung-Joo Hwang of Yonsei University has a long record in pharmaceutical formulation and drug delivery systems, Min-Soo Kim of Pusan National University is known for work on particle engineering and solid-state pharmaceutics, and Heejun Park of Duksung Women’s University contributes depth in formulation science and dosage form development. Their combined vision, as reflected in the topics outlined for the issue, is explicitly translational: the emphasis is not merely on elegant laboratory demonstrations but on approaches that can survive the journey from bench to manufacturing line to patient, a journey that defeats a large proportion of otherwise promising formulation strategies every year.

Among the six thematic pillars of the call for papers, the first concerns particle engineering approaches for enhancing solubility, stability, and bioavailability. This encompasses a suite of technologies that have matured considerably over the past two decades. Nanocrystal suspensions, in which drug particles are reduced to sizes below a few hundred nanometers, exploit the fact that dissolution rate increases as particle size decreases, following classical Noyes-Whitney relationships. Amorphous solid dispersions take a different route, locking a drug molecule in a disordered, high-energy glassy state rather than its thermodynamically stable crystalline form, thereby achieving apparent solubility gains that can be orders of magnitude greater than the crystalline reference. Each strategy carries trade-offs: amorphous materials risk recrystallization during storage, while nanocrystals demand careful control of agglomeration, and the special issue is expected to showcase advances in managing precisely these vulnerabilities.

A second pillar covers advanced formulation strategies across the full spectrum of dosage routes, including oral, injectable, inhalable, and transdermal delivery, alongside broader advanced drug delivery systems. The significance of this breadth is hard to overstate. Oral solid dosage forms such as tablets and capsules still dominate the pharmaceutical market, but biologics, peptides, and RNA-based therapeutics are forcing the industry to rethink delivery entirely. Injectable long-acting formulations can sustain drug release for weeks or months from a single depot, transforming treatment adherence in conditions ranging from schizophrenia to HIV. Inhalable powders deliver drugs directly to the lung with particle size distributions engineered to deposit in specific airway regions, while transdermal systems bypass first-pass metabolism through the skin. Each route imposes its own particle-level requirements, from aerodynamic diameter in inhalation to needle-free injectability of suspensions, and formulation science sits at the intersection of all of them.

The third thematic area, solid-state characterization and control, addresses a subtler but equally critical dimension of drug development. Many drug molecules can exist in multiple crystalline forms, known as polymorphs, which differ in the packing arrangement of their molecules and consequently in their melting point, solubility, dissolution behavior, and mechanical properties. The regulatory and commercial stakes are enormous: a single unintended polymorph conversion can compromise a product’s performance or even trigger withdrawal from the market, a lesson etched into industry history by high-profile cases involving antiretroviral and antiulcer drugs. Modern characterization tools, including powder X-ray diffraction, differential scanning calorimetry, solid-state nuclear magnetic resonance, and vibrational spectroscopy, allow scientists to identify and monitor these forms with increasing precision, and the special issue will highlight how such analytical control is being embedded into development workflows rather than bolted on afterward.

Perhaps the most distinctive feature of the issue’s scope is its insistence on translational formulation science and scale-up. The pharmaceutical industry has long suffered from what researchers informally describe as the valley of death between formulation research and commercial manufacture: a nanosuspension that performs beautifully at the milliliter scale in a university laboratory may prove impossible to reproduce at the thousand-liter scale of a production facility, where mixing dynamics, heat transfer, and drying behavior behave entirely differently. Technologies such as hot-melt extrusion, spray drying, and high-pressure homogenization must be understood not just as laboratory tools but as industrial unit operations with their own engineering constraints. Contributions addressing how formulation designs survive this transition, how critical quality attributes are preserved during scale-up, and how development timelines can be compressed without sacrificing rigor are expected to form a core of the published collection.

Emerging manufacturing technologies constitute the fifth pillar, and this is where the field’s momentum is most visible. Continuous manufacturing, which replaces the traditional batch-based model with a steady flow of material through interconnected unit operations, is gaining regulatory acceptance and offers real-time quality control, smaller facility footprints, and faster response to demand. Additive manufacturing, including various forms of three-dimensional printing, opens the possibility of dosage forms with complex internal geometries tailored to release profiles that conventional compression cannot achieve, and in principle enables on-demand production of personalized doses. Alongside these, advances in microfluidic nanoparticle production and electrospinning are expanding the toolbox available to formulators. The special issue’s inclusion of commercial production among its interests signals that the editors want papers demonstrating not just feasibility but manufacturability.

The final thematic strand, Quality by Design and Process Analytical Technology, represents the intellectual framework that binds the others together. Quality by Design, or QbD, is a regulatory philosophy, codified in international guidance, that requires manufacturers to understand and control the relationships between formulation ingredients, process parameters, and product quality, rather than simply testing finished products and hoping for the best. Process Analytical Technology, or PAT, supplies the instruments that make this possible in practice: inline and online sensors such as near-infrared and Raman spectroscopy that monitor critical attributes in real time during manufacturing, feeding data into control systems that can adjust parameters on the fly. Together, QbD and PAT shift pharmaceutical development from an empirical, trial-and-error discipline toward a predictive, science-based engineering practice, and their application to particle engineering processes is an area of intense current research.

For the broader scientific community, the significance of this special issue lies in its timing and its framing. The pharmaceutical pipeline is increasingly dominated by molecules and modalities that stress every assumption of classical dosage form design: poorly soluble small molecules, large fragile biologics, nucleic acid therapeutics requiring lipid nanoparticles, and combination products that blur the line between drug and device. Meanwhile, regulators and health systems are demanding shorter development times, more robust supply chains, and dosage forms that improve patient adherence. Particle engineering and formulation science sit squarely at the confluence of these pressures, and the January 2027 issue of the Journal of Pharmaceutical Investigation, with submissions due by June 30, 2026, is positioned to become a landmark snapshot of how the discipline is converting laboratory insight into medicines that patients can actually benefit from. Researchers working across solubility enhancement, solid-state science, manufacturing innovation, and quality systems now have a clearly defined venue to present that translational story in full.

Subject of Research: Translational pharmaceutical formulation and particle engineering for drug dosage form development

Article Title: Special Issue: Translational Advances in Pharmaceutical Dosage Form Development Based on Particle Engineering and Formulation Science

Article References: Special Issue: Translational Advances in Pharmaceutical Dosage Form Development Based on Particle Engineering and Formulation Science. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: particle engineering, formulation science, drug delivery, solubility enhancement, bioavailability, solid-state characterization, polymorphism, Quality by Design, Process Analytical Technology, continuous manufacturing, scale-up, Journal of Pharmaceutical Investigation

Short tandem repeats, or STRs, are stretches of DNA in which a short sequence of two to six base pairs repeats over and over. The number of repeats at any given locus varies from person to person, which is precisely what makes STRs the backbone of modern forensic DNA profiling. Because these repeat counts are inherited, one copy from each parent, they allow investigators to compare a crime scene sample with a suspect’s profile, or to establish biological relationships in paternity cases. But the statistics underpinning those comparisons are only valid if laboratories know how common each repeat variant, or allele, is in the relevant population. A profile match that looks overwhelming in one population may carry different weight in another, which is why population-specific frequency databases are a cornerstone of ethical and accurate forensic practice.

The research team, led by Brajesh Kumar and Amitabh Biswas of Galgotias University’s School of Forensic Sciences, together with colleagues from the Central Forensic Science Laboratory in Chandigarh, Ingenomics India, and the Regional Forensic Science Laboratory in Jabalpur, used the Ingenomics AutoProfiler STR Kit to amplify all 24 markers simultaneously. This six-dye multiplex system, which was independently validated for forensic applications, covers the expanded set of loci now favored internationally, including the highly variable SE33 and Penta E markers alongside familiar names such as FGA, vWA, and TH01. Genotyping was carried out by capillary electrophoresis, and the resulting allele calls were subjected to statistical analysis using established population genetics software, including Arlequin, GenAlEx, and PowerStats.

The headline numbers are striking. Across the 24 loci, the probability of match, which expresses the chance that two randomly selected unrelated individuals share the same genotype, ranged from 0.012 to 0.186. Inverted into its more familiar form, the power of discrimination ranged from 0.814 to 0.988, meaning the best markers could distinguish between any two individuals in the population with near certainty. SE33 topped the list with a discrimination power of 0.988, followed closely by Penta E at 0.983 and FGA at 0.962. At the other end of the spectrum, CSF1PO at 0.814 and D2S441 at 0.844 were comparatively modest performers, a pattern consistent with their lower allelic diversity in populations worldwide.

Polymorphism information content, a measure of how informative a marker is for linkage and identity analysis, ranged from 0.601 to 0.933, with the majority of loci exceeding 0.7, a threshold conventionally regarded as indicating high polymorphism. Gene diversity values, which capture the expected heterozygosity at each locus, spanned 0.666 to 0.939, confirming that the Santhal sample carries substantial genetic variability. Observed and expected heterozygosities were calculated for every locus, and tests against Hardy-Weinberg equilibrium were performed to verify that allele frequencies behave as expected under random mating, a critical quality check before any forensic statistic can be considered reliable.

For paternity testing, the study’s parameters matter even more directly. The power of exclusion, the probability that a randomly selected man would be excluded as the biological father of a child, ranged from 0.428 to 0.913 across individual loci, with SE33 and Penta E showing the strongest exclusion capacity. The typical paternity index varied from 1.667 to 11.667, again led by the most polymorphic markers, including SE33, Penta E, and D12S391. When the loci were combined, the results became extraordinary: the combined power of exclusion reached 0.999999999991, the combined paternity index stood at 3.51 multiplied by ten to the tenth power, and the combined probability of match fell to 2.41 multiplied by ten to the power of negative 28. The combined power of discrimination, rounded, was effectively 1. In practical terms, the chance that two unrelated Santhal individuals would share an identical 24-locus profile is so vanishingly small that a matching profile constitutes evidence of identity at a level few other forms of forensic evidence can approach.

Why does population-specific data of this kind matter so much? Forensic statistics rest on the product rule: the rarity of a full profile is estimated by multiplying the frequencies of the individual alleles, an operation that assumes statistical independence within the population under consideration. If a population has a history of endogamy, consanguinity, or founder effects, as many isolated or semi-isolated communities do, allele frequencies can drift in ways that inflate or deflate match probabilities. The Santhal, an Austroasiatic-speaking tribal community with a distinct demographic history in eastern India, are precisely the kind of population for which generic national databases may not be adequate. By generating a dedicated allele frequency dataset, the study gives forensic practitioners in Bihar and neighboring states a defensible statistical foundation when the source of a sample may belong to this community.

The work also contributes to the broader scientific picture of Indian genetic diversity. Previous studies have documented STR polymorphism in Chhattisgarh, Himachal Pradesh, northwestern India, and among the Sindhi population, and genomic research on Austroasiatic speakers has highlighted the role of landscape barriers and sex-specific admixture in shaping their genetic structure. Each new population dataset refines the map of how genetic variation is distributed across the subcontinent, and the Santhal data will allow comparisons that illuminate both forensic and anthropological questions. The authors note that the 24 loci are highly informative not only for individual identification but also for kinship analysis, extending their utility to disaster victim identification, missing persons investigations, and complex relationship testing.

The study was approved by the Institutional Ethics Committee of Apex Hospital in Varanasi, and the authors report no conflicts of interest and no external funding. All participants were unrelated volunteers who consented to contribute samples, and the authors acknowledge their role in enabling the research. The sampling strategy, restricted to unrelated individuals, is essential for Hardy-Weinberg testing and for ensuring that the frequency estimates reflect the general population rather than clustered family lineages.

As DNA evidence continues to expand its role in the Indian judicial system, studies like this one quietly underpin every statistic that appears in a courtroom report. A match probability of ten to the negative 28 is only as credible as the allele frequency table behind it, and that table must reflect the population to which a suspect or victim belongs. With the Santhal community now represented in the forensic literature by a rigorously characterized 24-locus dataset, investigators and courts in Bihar gain a resource that makes DNA statistics for this population both more accurate and more defensible. It is a reminder that the power of forensic genetics depends not just on the chemistry of amplification and detection, but on the patient, community-by-community work of measuring human variation itself.

Subject of Research: Forensic genetic profiling of autosomal STR markers in the Santhal tribal population of Bihar, India

Article Title: Allele frequency distribution and forensic efficiency parameters of 24 autosomal STR markers in the santhal tribal community of Bihar, India

Article References: Kumar, B., Biswas, A., Dixit, S., Sharma, S., & Shrivastava, P. (2026). Allele frequency distribution and forensic efficiency parameters of 24 autosomal STR markers in the santhal tribal community of Bihar, India. The Science of Nature, 113(6), Article 125. https://doi.org/10.1007/s00114-026-02176-2

Image Credits: AI Generated

DOI: 10.1007/s00114-026-02176-2

Keywords: forensic genetics, STR markers, Santhal, allele frequency, paternity testing, population genetics, India, DNA profiling, Hardy-Weinberg equilibrium, power of discrimination, tribal population, polymorphism