Poor pharmaceutical material properties of active pharmaceutical ingredients (APIs) can result in suboptimal manufacturing and therapeutic outcomes. Rivaroxaban (RIV) was explored as a model API due to its poor pharmaceutical properties and challenging industrial processability. In this research, crystal habit modification (CHM) of RIV was explored via solvent evaporation, cooling crystallization, and sonocrystallization methods. RIV (irregular) habit was modified to cuboidal, plate, and fiber via solvent evaporation; however, these were not further explored due to their large crystal sizes (>400 µm), which could pose serious dissolution and dose uniformity issues. Cooling crystallization method yielded plate (RIV_ACT) and blade-shaped (RIV_ACN) crystals with sizes < 200 µm. Further, CHM by sonocrystallization yielded tabular (RIV_SN6) crystals < 10 µm in size, which also exhibit a lower aspect ratio, a lower span value, and a narrower crystal size distribution than RIV_ACT and RIV_ACN. No polymorphic changes in modified habits were observed, as confirmed by PXRD, DSC, and TGA. Powder flowability improved significantly in the RIV_SN6 than in RIV_ACT and RIV_ACN (p < 0.0001) due to its narrow crystal size distribution. Interestingly, the RIV_SN6 showed improved tensile strength (p < 0.05) at a compression force of 300 MPa and exhibited improved wettability due to the exposure of polar functional groups on the modified habits. Furthermore, significant improvements in polar energy (p < 0.05) and ∼1.88 fold of IDR (p < 0.0001) were observed in RIV_SN6 compared to the RIV_ACT and RIV_ACN due to the prominence of polar groups and hydrophilic components on the particular facet.

Istradefylline (IDF), a selective adenosine A2A receptor antagonist, is used as adjunct therapy to manage motor fluctuations in Parkinson's disease. However, its clinical efficacy is limited by poor aqueous solubility, as it belongs to Biopharmaceutical Classification System (BCS) Class II. To overcome this limitation, IDF nanocrystals (IDF-NC) were developed using the nanoprecipitation technique with polyvinyl alcohol (PVA) as a stabilizer. Formulation parameters were initially screened using Plackett-Burman design and subsequently optimized via Box-Behnken design under Response Surface Methodology. The optimized IDF-NC demonstrated an average particle size of 185.33 +/- 20.85 nm, a polydispersity index of 0.212 +/- 0.050, and cuboidal morphology was confirmed by electron microscopic analysis. Thermal and structural characterization confirmed the preservation of crystallinity and absence of chemical interactions. In vitro drug release studies showed a similar to 6-fold increase in dissolution rate for IDF-NC compared to IDF. The nanocrystals were incorporated into a hydrogel base, which exhibited pseudoplastic behavior and suitable spreadability for transdermal application. Ex vivo permeation studies revealed that microneedling significantly enhanced drug permeation, achieving 62.16 +/- 1.73% permeation compared to 23.49 +/- 1.82% without microneedling. Overall, the combination of nanocrystal technology and microneedle-assisted delivery represents a promising strategy to enhance the transdermal bioavailability of poorly soluble drugs. These findings support further exploration through in vivo pharmacokinetic and pharmacodynamic evaluations.

Powder flowability of active pharmaceutical ingredients (APIs) plays a paramount role during tablet manufacturing as many APIs show poor flowability and compressibility. Coprocessing of drugs by quasi-emulsion solvent diffusion (QESD) process is an effective strategy to improve its powder flowability and compressibility. In this study, ethambutol hydrochloride (ETB), an anti-tubercular drug was coprocessed with hydroxypropyl methyl cellulose (HPMC) E15 at 2.5 % w/v concentration following the novel QESD methodology. Optimization of process parameters is an essential step before proceeding for scale-up batches. Hence, the effect of process parameters on the spherical agglomerates was explored by design of experiment (DoE) approach. Central composite design (CCD) was employed to study the effect of important process parameters on the quality attributes of the spherical agglomerates. Statistical analysis by standard least square method revealed that aqueous phase: organic phase (AP:OP) ratio and stirring rate had most significant impact (p < 0.05) on span, bulk density, circularity, and yield of the agglomerates. The powder flowability was predominantly dependent on the agglomerate circularity, followed by bulk density and span. It was found that powder samples with reduced circularity showed cohesive nature as indicated by Carr's index calculation. Spectral and thermal analysis of the agglomerates revealed no changes in the solid-state of ETB. Also, no changes were noticed in the dissolution profile of tablets prepared from the spherical agglomerates of different batches. The influence of QESD process parameters on the quality attributes of agglomerates were statistically evaluated and a desirability of 0.88 was obtained indicating good prediction accuracy.

Carbon quantum dots (CQDs) are widely explored for bioimaging, drug delivery, and theranostic applications due to their tunable fluorescence, biocompatibility, and adaptable surface chemistry. Nevertheless, precise hydrophobic-hydrophilic tuning from a single precursor remains underdeveloped, as most approaches depend on postsynthetic modification or multiple carbon sources, which can introduce additional processing steps and variability in surface composition. A single-precursor strategy may help simplify the synthesis and provide more consistent control over surface functionalities, offering a more direct route to polarity-tuned CQDs. Herein, we report a single-precursor-directed strategy to generate CQDs with distinct surface polarities, enabling controlled spatial organization within liposomal nanostructures. Curcumin was utilized as the carbon source in a solvothermal process conducted in the absence and presence of 3-aminopropyltrimethoxysilane, producing hydrophobic (Hb-CQD) and hydrophilic (Hp-CQD) carbon dots, respectively. The engineered polarity contrast dictated their interfacial behavior: Hb-CQDs preferentially embedded within the hydrophobic lipid bilayer (L-Hb-CQD), Hp-CQDs localized in the aqueous core of liposomes (L-Hp-CQD), and liposome-in-liposome (L-Hb-CQD-in-L-Hb-CQD) system. Encapsulation conditions were optimized to ensure homogeneous dispersion, improved colloidal stability, and enhanced intrinsic fluorescence of both CQD systems. Encapsulation efficiency, structural integrity, and spatial localization were systematically verified using fluorescence spectroscopy, TEM, and confocal laser scanning microscopy. The polarity control from a unified precursor platform demonstrates a rational route for directing nanoscale positioning of carbon dots within biomimetic architectures. The approach provides a versatile framework for designing multifunctional nanohybrids with potential applications in advanced bioimaging, controlled drug delivery, integrated theranostics, and mechanistic studies of nanoparticle-membrane interactions.

Crystal habit modification potentially improves the pharmaceutical and biopharmaceutical properties related to active pharmaceutical ingredients (APIs) and is an important aspect of crystal engineering.

Active pharmaceutical ingredient (API) coprocessing technique such as quasi-emulsion solvent diffusion (QESD) is gaining prominence as an alternative to granulation for improving powder flowability and tablet manufacturability. Current research provides a novel methodology to coprocess ethambutol hydrochloride (ETB) with HPMC-E polymer to obtain spherical agglomerates. Different HPMC-E polymer grades (E5, E15 and E50) were used at different concentrations (1 %w/v, 2.5 %w/v, and 5 %w/v) to assess its impact on the coprocessing. All coprocessed QESD samples performed significantly better than ETB-API in terms of flowability improvement by angle of repose (p < 0.01), Carr's index (p < 0.05). PXRD, DSC, and FTIR analyses indicated no solid-state changes in coprocessed ETB. The QESD samples could be compacted into tablets of sufficient tensile strength (>1.7 MPa) by direct compression method. Though intrinsic dissolution rate was lower for coprocessed API, tablet dissolution studies revealed no effect on the dissolution profile with similar to 95 % of ETB dissolution within 30 mins of the study.

The field of machine learning (ML) is advancing to a larger extent and finding its applications across numerous fields. ML has the potential to optimize the development process of microneedle patch by predicting the drug release pattern prior to its fabrication and production. The early predictions could not only assist the in-vitro and in-vivo experimentation of drug release but also conserve materials, reduce cost, and save time. In this work, we have used a dataset gleaned from the literature to train and evaluate different ML models, such as stacking regressor, artificial neural network (ANN) model, and voting regressor model. In this study, models were developed to improve prediction accuracy of the in-vitro drug release amount from the hydrogel-type microneedle patch and the in-vitro drug permeation amount through the micropores created by solid microneedles on the skin. We compared the performance of these models using various metrics, including R-squared score (R2 score), root mean squared error (RMSE), and mean absolute error (MAE). Voting regressor model performed better with drug permeation percentage as an outcome feature having RMSE value of 3.24. In comparison, stacking regressor have a RMSE value of 16.54, and ANN model has shown a RMSE value of 14. The value of permeation amount calculated from the predicted percentage is found to be more accurate with RMSE of 654.94 than direct amount prediction, having a RMSE of 669.69. All our models have performed far better than the previously developed model before this research, which had a RMSE of 4447.23. We then optimized voting regressor model’s hyperparameter and cross validated its performance. Furthermore, it was deployed in a webapp using Flask framework, showing a way to develop an application to allow other users to easily predict drug permeation amount from the microneedle patch at a particular time period. This project demonstrates the potential of ML to facilitate the development of microneedle patch and other drug delivery systems.

Dapagliflozin propanediol monohydrate (DAPA), an antidiabetic drug owing to its needle-shaped crystals exhibits poor micromeritic and physicochemical properties. Crystal habit modification by conventional and sonocrystallization approaches was employed to improve its manufacturability. SEM analysis of sonocrystallized DAPA in acetonitrile (DAPA_SNC3) revealed a rod habit with lower aspect ratio (3.56±0.91) and narrow size distribution (span value-1.37). In case of DAPA_EH and DAPA_CS (solvent evaporation in ethanol:n-hexane, and chloroform, respectively), rod and plate-shaped crystals were obtained with aspect ratios 6.98±5.84 and 6.03±4.21, respectively. All three samples showed significantly improved powder flowability (p<0.0001) compared to DAPA. Further solid-state characterization by FTIR, TGA, DSC, and PXRD showed no polymorphic changes in recrystallized samples. The contact angle studies in water revealed wetting tendency in the following order: SONO_SNC3>SONO_EH>SONO_CS>DAPA. Polar energies of DAPA_SNC3 and DAPA_CS were significantly higher (p<0.01 & p<0.001, respectively) when compared with DAPA. The XPS studies showed increased hydrophilic elements on the surfaces of DAPA_SNC3 crystals which resulted in improved wettability. DAPA_SNC3 among all samples showed highest tensile strength at 200MPa compression force because of its shape. DAPA_EH showed no significant improvement in IDR profile, while DAPA_CS and DAPA_SNC3 showed significantly faster IDR because of prominent polar functionality (p<0.05 and p<0.0001, respectively).

Active pharmaceutical ingredients (API) with unfavorable physicochemical properties and stability present a significant challenge during their processing into final dosage forms. Cocrystallization of such APIs with suitable coformers is an efficient approach to mitigate the solubility and stability concerns. A considerable number of cocrystal-based products are currently being marketed and show an upward trend. However, to improve the API properties by cocrystallization, coformer selection plays a paramount role. Selection of suitable coformers not only improves the drug's physicochemical properties but also improves the therapeutic effectiveness and reduces side effects. Numerous coformers have been used till date to prepare pharmaceutically acceptable cocrystals. The carboxylic acid-based coformers, such as fumaric acid, oxalic acid, succinic acid, and citric acid, are the most commonly used coformers in the currently marketed cocrystal-based products. Carboxylic acid-based coformers are capable of forming the hydrogen bond and contain smaller carbon chain with the APIs. This review summarizes the role of coformers in improving the physicochemical and pharmaceutical properties of APIs, and deeply explains the utility of afore-mentioned coformers in API cocrystal formation. The review concludes with a brief discussion on the patentability and regulatory issues related to pharmaceutical cocrystals.

Stability is an essential quality attribute of any pharmaceutical formulation. Poor stability can change the color and physical appearance of a drug, directly impacting the patient's perception. Unstable drug products may also face loss of active pharmaceutical ingredients (APIs) and degradation, making the medicine ineffective and toxic. Moisture content is known to be the leading cause of the degradation of nearly 50% of medicinal products, leading to impurities in solid dose formulations. The polarity of the atoms in an API and the surface chemistry of API particles majorly influence the affinity towards water molecules. Moisture induces chemical reactions, including free water that has also been identified as an important factor in determining drug product stability. Among the various approaches, crystal engineering and specifically co-crystals, have a proven ability to increase the stability of moisture-sensitive APIs. Other approaches, such as changing the salt form, can lead to solubility issues, thus making the co-crystal approach more suited to enhancing hygroscopic stability. There are many reported studies where co-crystals have exhibited reduced hygroscopicity compared to pure API, thereby improving the product's stability. In this review, the authors focus on recent updates and trends in these studies related to improving the hygroscopic stability of compounds, discuss the reasons behind the enhanced stability, and briefly discuss the screening of co-formers for moisture-sensitive drugs.

Active Pharmaceutical Ingredients (APIs) do not always exhibit processable physical properties, which makes their processing in an industrial setup very demanding. These issues often lead to poor robustness and higher cost of the drug product. The issue can be mitigated by co-processing the APIs using suitable solvent media-based techniques to streamline pharmaceutical manufacturing operations. Some of the co-processing methods are the amalgamation of API purification and granulation steps. These techniques also exhibit adequate robustness for successful adoption by the pharmaceutical industry to manufacture high quality drug products. Spherical crystallization and co-precipitation are solvent media-based co-processing approaches that enhances the micromeritic and dissolution characteristics of problematic APIs. These methods not only improve API characteristics but also enable direct compression into tablets. These methods are economical and time-saving as they have the potential for effectively circumventing the granulation step, which can be a major source of variability in the product. This review highlights the recent advancements pertaining to these techniques to aid researchers in adopting the right co-processing method. Similarly, the possibility of scaling up the production of co-processed APIs by these techniques is discussed. The continuous manufacturability by co-processing is outlined with a short note on Process Analytical Technology (PAT) applicability in monitoring and improving the process.

Amorphous solid dispersions enhance solubility and oral bioavailability of poorly water-soluble drugs. The escalating number of drugs with poor aqueous solubility, poor dissolution, and poor oral bioavailability is an unresolved problem that requires adequate interventions. This review article highlights recent solubility and bioavailability enhancement advances using amorphous solid dispersions (ASDs). The review also highlights the mechanism of enhanced dissolution and the challenges faced by ASD-based products, such as stability and scale-up. The role of process analytical technology (PAT) supporting continuous manufacturing is highlighted. Accurately predicting interactions between the drug and polymeric carrier requires long experimental screening methods, and this is a space where computational tools hold significant potential. Recent advancements in data science, computational tools, and easy access to high-end computation power are set to accelerate ASD-based research. Hence, particular emphasis has been given to molecular modeling techniques that can address some of the unsolved questions related to ASDs. With the advancement in PAT tools and artificial intelligence, there is an increasing interest in the continuous manufacturing of pharmaceuticals. ASDs are a suitable option for continuous manufacturing, as production of a drug product from an ASD by direct compression is a reality, where the addition of multiple excipients is easy to avoid. Significant attention is necessary for ongoing clinical studies based on ASDs, which is paving the way for the approval of many new ASDs and their introduction into the market.