Classification system proposed to guide the design, development, regulatory approval, and scaling of long acting, small- and macro-molecule parenteral products (CS-BLAP).

Amiodaron is a broad-spectrum antiarrhythmic drug that is widely used in the management of various cardiac rhythm disorders, including ventricular and supraventricular arrhythmias. Despite its therapeutic effectiveness, Amiodaron presents complex physicochemical characteristics that pose significant challenges in the development of oral solid dosage forms, particularly tablet preparations. Therefore, a comprehensive pre-formulation study is essential to ensure the development of stable, safe, and effective pharmaceutical products. This study aims to examine the pre-formulation aspects of Amiodaron hydrochloride as a scientific basis for tablet formulation development. The research method employed was a literature-based study focusing on the physicochemical properties of Amiodaron, including ionization constants (pKa), partition coefficients (log P), solubility, dissolution behavior, polymorphism, chemical and physical stability, as well as particle and powder characteristics. Relevant data were obtained from scientific journals, pharmacopeias, and authoritative pharmaceutical references. The results indicate that Amiodaron hydrochloride is classified as a Biopharmaceutics Classification System (BCS) class II drug, characterized by low aqueous solubility and high membrane permeability. The compound is highly lipophilic, weakly basic, and sensitive to environmental factors such as light, heat, and alkaline pH conditions, which may lead to degradation. Furthermore, Amiodaron powder exhibits poor flowability and compressibility, making direct compression during tablet manufacturing difficult. Based on these findings, appropriate formulation strategies are required, including the use of inclusion complexes, hydrophilic polymers, granulation techniques, and careful selection of excipients to enhance solubility, stability, and bioavailability. This pre-formulation study is expected to provide a strong scientific foundation for the development of optimal Amiodaron tablet formulations.

Objective One of the significant problems associated with poorly soluble drugs is low bioavailability. Butenafine HCl is classified as BCS Class II by the biopharmaceutical classification system, with low solubility and high permeability. Objectives: Formulation as a nanosuspension is an attractive and promising alternative to solve low solubility problems and low bioavailability Methods: A nanosuspension of Butenafine HCL was generated utilizing a bottom-up method through the solvents/anti-solvents procedure characterized by particle size analysis, polydisperse index, and entrapment efficacy, and then the selected formula was described by dissolution testing, differential scanning calorimetry, X-ray powder diffraction, FTIR, and FESEM. Nanosuspensions were prepared via the solvent/anti-solvent procedure, using different polymer types and ratios. Results: Butenafine solubilized in PBS with 1% soluplus, PVP, PEG 400, and poloxamer was 14.32 ±0.011,6±0.01,10.48±0.012, and 2.025±0.001.To form a nanosuspension with particle sizes ranging from 78 to 516 ±0.01 nm, entrapment up to 96%, and a Drug content of 99%. Particle size of optimum formula, consisting of Butenafine HCL and soluplus® in a ratio of drug: stabilizer (Soluplus®):co-stabilizer (PEG400) is (1:8:2.5) measured in nanostructure, and it was equal to 78.3±0.03 with a PDI 0.2511±0.13, which is in the nanosized range, drug content of optimum formula 99.6±0.013, and entrapment was 96±0.012. Osmolarity adjusted to a range of 280 to 310 mOsm/Kg. The release of the drug after 120 min was 95%. FTIR spectra show a distinct peak for the drug, indicating no chemical interaction between BF and Soluplus®.DSC shows a slight shift in the melting point to 220.50 °C due to the presence of cryoprotectants. PXRD shows amorphous formation due to nanosuspension, and FESEM shows the size and shape of the nanosuspension, in which the size of the particle by FESEM was 72.9nm, which is close to the measured particle size. The stability study of the optimal formula after three months showed a particle size of 78 nm at 5 °C and 80nm at 25 °C . Conclusions: Using soluplus as a stabilizer at various concentrations successfully produced a nanosuspension of Butenafine HCl.The best formula, consisting of Butenafine HCL and soluplus® in a ratio of drug: stabilizer (Soluplus®):co-stabilizer (PEG400) is 1:8:2.5,

Mesalamine premix-based delayed release formulation and its efficacy assessment using a 3D in-vitro gut model for inflammatory bowel disease.

The challenges with bioavailability and solubility associated with drugs categorized as Class II under the BCS stand for the Biopharmaceutical Classification System. Such medications, which possess low solubility in water along with high permeability,provide significant challenges for therapeutic efficacy and drug development.Polymer nanofibers are growing nowadays because of their unique characteristics, which include a higher surface area-to-volume ratio and high porosity. The formulations corresponding to the small fibers have emerged as novel approaches to improve drug solubility, rate of dissolution, and overall bioavailability. The review begins by defining the essential concerns regarding BCS Class II drugs and the impact of insufficient solubility on their therapeutic effectiveness. Subsequently, the fact that it offers an in-depth review of multiple techniques for creating nanofibers, including melting, centrifugal jet spinning, and electrospinning, focuses on the way these techniques operate for protecting and delivering medications that are poorly soluble in water. Furthermore, the review discusses the potential for improving drug solubility and the compatibility of various polymers, such as copolymers andnanocomposites, with BCS Class II drugs in nanofiber formulations. Polymers are essential to the fabrication of nanofibers; they are employed in tissue engineeringscaffolds, wound dressings, and biomedical applications. Several variables involving needle diameter, rate of flow, the voltage applied, needle-to-collector distance,solvent polymer concentration, viscosity, temperature, and humidity directly impact the performance of electrospun nanofibers. Several studies, including solubility,drug release kinetics, the techniques of Fourier transform infrared spectroscopy(FTIR), and scanning electron microscopy (SEM), are utilized for characterizing electrospun nanofibers. A comprehensive investigation involving in vitro and in vivo studies provides illumination on the extent to which drug delivery systems developed with nanofibers function. This review concludes by compiling the most recently published studies on nanofiber-based methods to improve BCS Class II medication's solubility and bioavailability. The main objective of the work here is to lead scientists researching pharmaceuticals toward the efficient use of nanofiber technologies that will improve drug delivery’s effectiveness.

The results of studying solid dispersions of quercetin aimed at improving its biopharmaceutical properties are presented. Quercetin belongs to Class IV of the Biopharmaceutics Classification System and is characterized by low solubility and permeability, which limits its bioavailability. To enhance its therapeutic effectiveness, solid dispersions were prepared with various polymeric carriers such as polyethylene glycol (PEG-4000), hydroxypropyl methylcellulose (HPMC), mannitol, polyvinylpyrrolidone K30 (PVP K30), and cetostearyl alcohol in 1:1 ratio. The physicochemical properties of the obtained samples were evaluated using spectrophotometry, X-ray diffraction analysis, thermal analysis, and scanning electron microscopy. It was found that the use of polymeric carriers promotes the amorphization of quercetin and improves its solubility. The highest degree of amorphization was achieved in the sample with PVP K30, as confirmed by both X-ray diffraction and thermal analysis. PEG-4000 and mannitol demonstrated moderate effectiveness, whereas cetostearyl alcohol proved unsuitable due to thermal instability and the formation of dense agglomerates, which slow down the release of the active substance. Biopharmaceutical studies demonstrated a significant increase in solubility and a reduction in the dose number in solid dispersions compared to the native substance. The most promising solid dispersions turned out to be those in which PVP K30 was used as a carrier for the gastric environment and mannitol for the intestinal environment. The obtained results indicate that the development of solid dispersions is an effective strategy for enhancing the bioavailability of poorly soluble compounds, particularly quercetin, and may be applied in the design of new oral dosage forms.

We report a modified bicomponent solid-state form of tadalafil (TDF) and finasteride (FNS), prepared at a 1:1 molar stoichiometric ratio, corresponding to the USFDA-approved combination marketed under the trade name Entadfi, for the treatment of benign prostatic hyperplasia. Individually, both constituent drugs suffer from the limitation of low aqueous solubility, belonging to class-II of the biopharmaceutical classification system. A drug-drug coamorphous system of TDF and FNS was prepared by mechanochemical synthesis. Characterization of this novel phase was carried out by powder X-ray diffraction, thermal analysis, and FT-IR spectroscopy. Particle characteristics and morphological features of the coamorphous system were studied by scanning electron microscopy and 3D-laser scanning microscopy. Possible intermolecular interactions between TDF and FNS, facilitating the formation of the coamorphous phase, as indicated by spectroscopic analysis, were validated by the computational study employing density functional theory. Interestingly, in vitro dissolution studies showcased significant improvement in the dissolution profile of the coamorphous system compared with the physical mixture, which was successfully translated to the in vivo study in SD rats. Physical stability of the developed coamorphous system evaluated under accelerated as well as long-term stability conditions indicated reasonable stability for potential drug product usage. Considering its industrial applicability due to obvious benefits, viz., single solid phase, improved solubility, dissolution, and better pharmacokinetic parameters leading to higher bioavailability, the developed coamorphous system could prove to be a better therapeutic alternative over the marketed physical mixture.

Elagolix, a first-in-class, orally active, non-peptide gonadotropin-releasing hormone (GnRH) antagonist transformed the treatment for endometriosis and uterine fibroids. Unlike traditional peptide-based GnRH agonists that require parenteral administration and induce initial hormonal flares, elagolix offers dose-dependent estrogen suppression with rapid reversibility. This review analyzes the pharmaceutical and biopharmaceutical attributes that facilitate the oral delivery of this peptide-mimetic small molecule. This work provides the physicochemical profile of elagolix sodium, highlighting its classification as a Biopharmaceutics Classification System (BCS) Class II compound and the implications of its pH-dependent solubility on formulation strategies. Furthermore, the absorption, distribution, metabolism, and excretion (ADME) characteristics are detailed, elucidating the role of hepatic transporters and metabolic enzymes in its pharmacokinetic behavior. The review emphasizes recent advancements in analytical methodologies, including high-performance liquid chromatography (HPLC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), developed for the rigorous quantification of elagolix and its degradation products in complex matrices. Additionally, the implementation of Quality by Design (QbD) principles in optimizing formulation parameters and ensuring critical quality attributes is synthesized. This review explains the pivotal role of elagolix as a model for overcoming the barriers associated with the oral delivery of therapeutics targeting the GnRH receptor by integrating data on stability, solubility enhancement techniques, and regulatory considerations

Lapatinib ditosylate (LD) is a chemotherapeutic agent that belongs to Class II of the Biopharmaceutical Classification System. The objective of this work was to enhance oral bioavailability of LD by developing a nanoparticle solid dispersion. Lapatinib ditosylate nanoparticles (LDNP) were prepared by a combination of precipitation followed by high pressure homogenization. The optimized LDNP formulation, containing LD, hydroxypropyl methyl cellulose acetate succinate, Brij-35, and sodium lauryl sulfate in the ratio of 1:4:0.5:0.2, was found to provide an average particle size of 103 ± 4.6 nm after freeze drying. Scanning electron microscopy and solid-state characterization revealed rounded particles in an amorphous state. Nanonization significantly (p < 0.05) increased dissolution rate (90 ± 4.6% within 30 min) compared with the physical mixture (29 ± 1.3% in 30 min). Pharmacokinetic evaluations performed in Wistar rats showed 1.3- and 1.4-fold increase in C max and AUCtotal after LDNP administration compared with commercial formulation. LDNP demonstrated similar growth inhibition in oral carcinoma MOC2 and FaDu cells as that of LD solution. LDNP showed complete remission of xenografted oral cancer in a C57BL/6 mouse model after seven doses of 100 mg/kg LDNP. The LDNP formulation can be developed to enhance the oral bioavailability of LD for effective oral cancer treatment.

Zileuton nanocrystals alter intestinal phase I/II metabolic enzymes and epithelial permeability in a sex-dependent manner.

The formulation and manufacture of macromolecules for oral delivery present persistent challenges owing to high molecular weight, pH sensitivity and manufacturing complexity. Consequently, over 90% of FDA-approved biologics are administered by invasive methods. Buccal delivery offers a promising non-invasive alternative, as it bypasses first-pass metabolism, avoids gastrointestinal degradation, and can improve patient compliance. Here we evaluate isothermal dry particle coating (iDPC) as a scalable, solvent-free approach to enhance buccal permeation by forming ion-pair coatings on drug particles. In iDPC, centrifugal and gas-drag forces promote systematic collisions between host and guest particles, here vancomycin and L-glutamic acid, yielding uniform surface coverage that facilitates buccal permeation. This study utilised a Design of Experiments (DoE) methodology within a Quality by Design (QbD) framework to optimise iDPC processing for vancomycin, a Biopharmaceutics Classification System (BCS) Class III glycopeptide with poor oral bioavailability. A Central Composite Face (CCF) design was utilised to investigate the interactive effects of five critical process parameters (CPPs): pre-processing time, processing time, nitrogen flow rate, drum speed and amino acid concentration, on two critical quality attributes (CQAs): content uniformity and 60-minute permeation across TR146 buccal epithelium. Regression modelling identified that increases in L-glutamic acid concentration and drum speed were the key factors enhancing permeation, while processing time and drum speed were the key variables improving content uniformity. A predictive 4D design space identified operating regions with a high probability of simultaneously meeting prespecified targets (permeation ≥ 40% and RSD ≤ 5%). The models demonstrated strong fit (R2 = 0.767 for permeation; 0.774 for content uniformity), with non-significant lack-of-fit, and performance improved markedly, with content uniformity ranging from 0.93 to 6.29% RSD and permeation increasing from 36% to 60% under optimised conditions. Mechanistic analysis indicated that drag from the nitrogen curtain impacted the fluidisation of cohesive L-glutamic acid fine particles, while total energy input promoted deagglomeration and dispersion, thereby improving uniformity. These findings demonstrate that iDPC is a robust manufacturing approach for buccal delivery of biologics, providing controlled particle level modification without the use of solvents. The QbD-driven DoE establishes clear links between CPPs and CQAs, supports the development of control strategies, and provides a basis for regulatory flexibility in the non-invasive delivery of large molecule therapeutics.

This study aims to enhance the bioavailability and polymorphic stability of Ticagrelor, a metastable, low-soluble and low-permeable Biopharmaceutics Classification System Class IV drug, by exploring different formulation approaches. Ticagrelor was taken as a model drug for the enhancement of bioavailability and polymorphic stability. Initially, various techniques, such as micronization, amorphous solid dispersion (ASD), and Self-Microemulsifying Drug Delivery System, were evaluated for dissolution enhancement. Based on the improvement in dissolution rate, polymorphic stability, and process viability, an ASD technique was selected for dissolution enhancement of Ticagrelor. Co-povidone VA 64 and vitamin E TPGS were used as carriers for the preparation of Ticagrelor solid dispersion (SD) by the solvent evaporation technique. The formulation was optimized and further evaluated for dissolution performance in biorelevant media fasted state simulated gastric fluid and fasted state simulated intestinal fluid. The bioavailability of the Ticagrelor SD tablet formulation was compared with a conventional immediate release tablet formulation prepared by wet granulation process in line with reference product Brilinta® (AstraZeneca LP). In vivo pharmacokinetic (PK) studies were carried out in Wistar rats with due approval from ethics committees such as CPCSEA and IAEC (CPCSEA/DIPS/02/23/61). Patients are not involved in this study, hence informed consent not applicable. The relative bioavailability and peak plasma concentration (Cmax) of Ticagrelor SD formulation compared to conventional immediate release tablet formulation in line with Brilinta® (AstraZeneca LP) were found to be 141.61±2.29% and 137.0±0.59%, respectively. Further, based on a doseadjusted PKs study of Ticagrelor SD, a 70 mg Ticagrelor tablet formulated with the SD technique was found to be equivalent to a 90 mg dose of Ticagrelor conventional immediate release tablet formulation with a comparable Cmax, area under the curve (AUC)0-24, and AUC0-∞. Visual observation of the dissected gastric organ through a stereomicroscope revealed no redness or bleeding post-administration of Ticagrelor SD formulations. The SD technique with carrier co-povidone VA 64 and vitamin E TPGS prepared by the solvent evaporation process could yield a Ticagrelor formulation with improved bioavailability and polymorphic stability.

Abstract Naproxen (NPX) is a widely used nonsteroidal anti‐inflammatory drug (NSAID) with limited aqueous solubility, commonly formulated as its sodium salt (SNPX) to enhance dissolution and absorption. This study systematically examines the influence of the sodium counterion on the structural, supramolecular, and electronic properties of NPX. Comparative analyses are performed using single‐crystal X‐ray diffraction, Hirshfeld surface (HS) mapping, and topological evaluation via the quantum theory of atoms in molecules (QTAIM). Density functional theory (DFT) calculations at the M06‐2X/6‐311++G(d,p) level provided further insights into chemical reactivity through frontier molecular orbitals and molecular electrostatic potential (MEP) maps. Both NPX and SNPX crystallize in the monoclinic space group P2 1 with overall geometric similarity, though significant differences are observed in the carboxyl group. NPX is stabilized by O─H···O hydrogen bonds, while SNPX exhibits four nonequivalent O···Na electrostatic contacts in addition to C─H···π and C─H···O interactions. Electronic descriptors revealed that SNPX and NPX − are more reactive and polarizable than neutral NPX, consistent with enhanced solubility and pharmaceutical performance. These findings highlight the critical role of counterions in modifying supramolecular arrangements and physicochemical properties, reinforcing the importance of solid‐state characterization in the development of Biopharmaceutics Classification System (BCS) Class II drugs.

Nanocrystals have emerged as an interesting class of delivery systems to solubilize pharmaceuticals belonging to classes II and IV of the Biopharmaceutics Classification System (BCS). This can be attributed to their small size and high drug content. More than 20 nanocrystal formulations have already been approved by the Food and Drug Administration (FDA) for oral and parenteral administration, with additional clinical trials in progress. This review provides an update on FDA-approved nanocrystals and current literature findings on their production using bottom-up techniques. Controlling drug supersaturation is a key step in this context. The beneficial surface-to-volume ratio enhances the dissolution rate of drugs compared to their solid form. Most monocrystal studies focus on diseases related to cancer and inflammation. We have concentrated on these areas, as well as new strategies aimed at combining drugs, including co-crystallization of drugs in nano-forms. Finally, we reviewed targeting approaches proposed for nanocrystals, which are primarily based on two main strategies: either grafting a ligand onto their surface or incorporating them into natural or modified membranes to facilitate homing to specific cells or tissues.

Imatinib (IMT) is a small-molecule tyrosine kinase inhibitor that primarily targets platelet-derived growth factor receptor-β and related kinases. Beyond its established efficacy in chronic myeloid leukemia, IMT has also demonstrated therapeutic benefits in gastrointestinal stromal tumors, dermatofibrosarcoma, acute lymphoblastic leukemia, and as a second-line treatment for aggressive systemic mastocytosis or as an anti-Mycobacterium agent. From a physicochemical perspective, IMT exhibits poor aqueous solubility but high membrane permeability, classifying it as a Biopharmaceutics Classification System Class II compound. Pharmacokinetically, IMT shows variable oral absorption and a prolonged terminal half-life, resulting in dose-dependent systemic exposure. Despite relatively high oral bioavailability, its clinical use requires large doses to achieve therapeutic efficacy, underscoring the need for advanced drug delivery strategies. Nano- and microscale delivery systems offer promising approaches to enhance tumor-specific accumulation through the enhanced permeability and retention effect while mitigating resistance mechanisms. However, achieving high drug loading introduces formulation challenges, such as controlling particle size distribution, polydispersity, and scalability. Moreover, designing carriers capable of controlled release without premature leakage remains crucial for maintaining systemic bioavailability and therapeutic performance. Emerging delivery platforms—including polymeric, lipid-based, carbon-derived, and stimuli-responsive nanocarriers—have shown significant potential in overcoming these limitations. Such systems can enhance IMT’s bioavailability, improve selective tumor targeting, and minimize systemic toxicity, thereby advancing its translational potential. This review aims to highlight the different biomedical applications of IMT and off-label uses, and to discuss current advances in drug delivery to optimize its clinical efficacy and safety profile.

Piroxicam (PRX), a non-steroidal anti-inflammatory drug (NSAID), is classified as a biopharmaceutical classification system class II (high permeability and low solubility), which limits its bioavailability. Enhancement of the dissolution rate is a key strategy to enhance the absorption. Solid dispersion systems, particularly when combined with amphiphilic multiple co-block polymers, offer a promising approach to address this challenge. This study aimed to investigate the effect of Poloxamer 188 (P188) and the solid dispersion technique on the solubility and dissolution rate of PRX. Polyethylene glycol (PEG) 4000-based solid dispersions containing PRX were prepared using varying concentrations of Poloxamer 188 surfactant through the fusion method. The solid dispersions were evaluated for saturated solubility in water for 24 hours. Selected formulations were further characterized using thermal analysis and vibrational spectroscopy. The optimized solid dispersion formulation was filled into capsules, and a dissolution assay was carried out to compare its performance with that of pure PRX capsules. The optimized formula, comprising 3% P188 and PEG4000, demonstrated a significant enhancement in saturation solubility parameters (p &lt; 0.05), specifically the Cmax/S0 ratio. Additionally, dissolution testing showed a 22.22% increase in the dissolution rate of the PRX solid dispersion capsules compared to pure PRX capsules. In conclusion, P188-based solid dispersion containing PRX enhanced the solubility and dissolution rate, potentially improving therapeutic efficacy.

Context: Cocrystallization is a promising solid-state modification used to enhance the dissolution rate and solubility of poorly water-soluble drugs, such as carbamazepine. As a Biopharmaceutics Classification System class II antiepileptic drug, carbamazepine exhibits high permeability but low aqueous solubility. The enhancement of its dissolution rate through cocrystallization is primarily attributed to the formation of hydrogen bonds between carbamazepine and coformers. Aims: To systematically review the effects of various coformers on the dissolution rate of carbamazepine. Furthermore, virtual screening techniques were employed to identify the coformer that demonstrates the strongest binding affinity with carbamazepine, thereby indicating the most favorable cocrystal formation. Methods: Following PRISMA 2020 guidelines, studies (2013–2023) were retrieved from PubMed, ScienceDirect, and MDPI. Eligibility was determined using the PICO framework: Population—carbamazepine with low water solubility; Intervention—cocrystallization with various coformers; Comparison—pure carbamazepine; Outcome—enhanced dissolution rate. Study quality and bias risk were assessed with the American Dietetic Association checklist. Molecular docking using AutoDockTools 1.5.6 predicted coformer interactions. Results: From 6,536 records, 14 studies met the inclusion criteria. Cocrystals with salicylic acid, nicotinamide, and para-hydroxybenzamide consistently improved dissolution compared to pure carbamazepine. Virtual screening results indicated that the cocrystal with salicylic acid exhibited the most favorable binding free energy (-3.67 kcal/mol), suggesting strong intermolecular interactions conducive to cocrystal stability. Conclusions: Cocrystallization significantly enhances carbamazepine dissolution, with salicylic acid proving to be the most effective coformer. These findings support the potential application of cocrystals in improving the bioavailability of poorly soluble drugs.

Establishing clinically relevant dissolution specifications for prodrug bioequivalence risk assessment: Integration of a dissolution/permeation system with physiologically based biopharmaceutics modeling in abiraterone acetate.

Polymeric microarray patches for transdermal delivery of amodiaquine and artesunate: A novel strategy against Plasmodium falciparum

For several decades, generating salt forms of the active pharmaceutical ingredients (APIs) has remained the preferred approach for the pharmaceutical industries. The salt form of the APIs provides the advantage of improving the solubility and stability, enhancing the dissolution rate, permeability, manufacturing robustness, taste masking, and life cycle management. The pharmaceutical salts are the ionic compounds of a drug and its counterion. The counterions can be classified as anionic, cationic, organic anions, and aromatic sulfonates. The salt form of the drug does not exhibit pH-dependent solubility. Developing a salt form of the drug will improve the bioavailability of poorly soluble drugs belonging to the biopharmaceutical classification system (BCS) class II and IV. Around 50% of the solid oral dosage forms in the market utilize the salt form of the drug. Identifying the suitable salt form right in the early stages of development will eliminate the need for complex formulation platforms such as amorphous solid dispersions. Despite various advantages, a few limitations must be addressed, such as hygroscopicity, polymorphism, and counterions. The salt screening can be integrated with artificial intelligence (AI) and computational tools to accelerate development. The review article summarizes the principles, benefits, limitations, and future outlook for pharmaceutical salts.