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Nonracemic amisulpride (SEP‐4199) is an investigational 85:15 ratio of aramisulpride to esamisulpride and currently in clinical trials for the treatment of bipolar depression. During testing of SEP‐4199, a pharmacokinetic/pharmacodynamic (PK/PD) disconnect was discovered that prompted the development of a controlled‐release (CR) formulation with improved therapeutic index for QT prolongation. Observations that supported the development of a CR formulation included (i) plasma concentrations of amisulpride enantiomers were cleared within 24‐hours, but brain dopamine D2 receptor (D2R) occupancies, although achieving stable levels during this time, required 5 days to return to baseline; (ii) nonracemic amisulpride administered to non‐human primates produced significantly greater D2R occupancies during a gradual 6‐hour administration compared with a single bolus; (iii) concentration–occupancy curves were left‐shifted in humans when nonracemic amisulpride was gradually administered over 3 and 6 hours compared with immediate delivery; (iv) CR solid oral dose formulations of nonracemic amisulpride were able to slow drug dissolution in vitro and reduce peak plasma exposures in vivo in human subjects. By mathematically solving for a drug distribution step into an effect compartment, and for binding to target receptors, the discovery of a novel PK/PD model (termed here as Distribution Model) accounted for hysteresis between plasma and brain, a lack of receptor saturation, and an absence of accumulation of drug occupancy with daily doses. The PK/PD disconnect solved by the Distribution Model provided model‐informed drug development to continue in Phase III using the non‐bioequivalent CR formulation with diminished QT prolongation as dose‐equivalent to the immediate release (IR) formulation utilized in Phase II. [ABSTRACT FROM AUTHOR]

The development of numerous drugs is often arrested at clinical testing stages, due to their unfavorable biopharmaceutical characteristics. It is the case of fenretinide (4-HPR), a second-generation retinoid, that demonstrated promising in vitro cytotoxic activity against several cancer cell lines. Unfortunately, response rates in early clinical trials with 4-HPR did not confirm the in vitro findings, mainly due to the low bioavailability of the oral capsular formulation that was initially developed. Capsular 4-HPR provided variable and insufficient drug plasma levels attributable to the high hepatic first-pass effect and poor drug water solubility. To improve 4-HPR bioavailability, several approaches have been put forward and tested in preclinical and early-phase clinical trials, demonstrating generally improved plasma levels and minimal systemic toxicities, but also modest antitumor efficacy. The challenge is thus currently still far from being met. To redirect the diminished interest of pharmaceutical companies toward 4-HPR and promote its further clinical development, this manuscript reviewed the attempts made so far by researchers to enhance 4-HPR bioavailability. A comparison of the available data was performed, and future directions were proposed. [ABSTRACT FROM AUTHOR]

With the large‐scale development of drugs, understanding the drug phase behaviors in complex systems becomes more and more important. Among them, the solubility of drugs in biorelevant media needs to be urgently understood. To address this challenge, new strategies based on machine learning models are proposed. First, the strategy trains five machine learning models (extra trees [ET], gradient boosting [GB], k‐nearest neighbors [k‐NN], random forest [RF], and extreme gradient boosting [XGBoost]) based on 15 molecular descriptors of the drug molecular properties. The XGboost model was identified as the best predictive model for predicting drug solubility performance in various solvents. Next, the input feature vectors were expanded for machine learning using the MACCS chemical fingerprint coupled with the XGboost model. The MACCS chemical fingerprint coupled with XGboost model has significantly improved the prediction accuracy of drug solubility. This finding demonstrates that the proposed strategy has solubility prediction capability, which is expected to provide valid information for drug development and drug solvent screening. [ABSTRACT FROM AUTHOR]

The impact of the crystalline or amorphous structure of a solid on the solubility and pharmacokinetic properties of a drug candidate is always considered by the pharmaceutical industry during the development of a new drug; however, it is not so frequently considered during the early drug discovery process by organic and medicinal chemists, particularly those working in academia. We want to share, as an example, the false negative obtained in the biological testing of a solid sample of a tyrosine kinase inhibitor due to its unexpected crystallinity and lower solubility with respect to a solid amorphous batch of the same compound and the experimentation carried out to establish the origin of such a discrepancy. [ABSTRACT FROM AUTHOR]

The short precorneal residence time of ophthalmic drops is associated with their low absorption; therefore, the development of ocular inserts capable of prolonging and controlling the ophthalmic release of drugs is an interesting option in the design and development of these drugs. A surface response design was developed, specifically the Central Composite Design (CCD), to produce ophthalmic films loaded with Dexamethasone (DEX) by the solvent evaporation method having experimental levels of different concentrations of previously selected polymers (PVP K-30 and Eudragit RS100.). Once optimization of the formulation was obtained, the in vivo test was continued. The optimal formulation obtained a thickness of 0.265 ± 0.095 mm, pH of 7.11 ± 0.04, tensile strength of 15.50 ± 3.94 gF, humidity (%) of 22.54 ± 1.7, mucoadhesion strength of 16.89 ± 3.46 gF, chemical content (%) of 98.19 ± 1.124, release of (%) 13,510.71, and swelling of 0.0403 ± 0.023 g; furthermore, in the in vivo testing the number and residence time of PMN cells were lower compared to the Ophthalmic Drops. The present study confirms the potential use of polymeric systems using PVPK30 and ERS100 as a new strategy of controlled release of ophthalmic drugs by controlling and prolonging the release of DEX at the affected site by decreasing the systemic effects of the drug. [ABSTRACT FROM AUTHOR]

Recently, the co-crystallization of pharmaceutical drugs is gaining consideration because it is an environmentally friendly and potentially effective technique to improve the solubility and bioavailability of poorly soluble drugs without altering the chemical identity or reducing the biological activity or therapeutic effect of the active pharmaceutical ingredient (API). The co-crystallization process in the pharmaceutical industry is still not fully utilized owing to the limited methods for large-scale production. However, it is a very convenient, appropriate, and green technique in the field of drug development research as only a few synthetic steps are involved with the minimal or no use of solvents. Herein, the selection criteria or the factors that affect the selection of coformers in this process are discussed. In addition, the different stages of co-crystal manufacturing, from the screening phase to industrial production, are identified and the use of continuous and scalable methods in co-crystal production as well as the implementation of quality-by-design and process analytical technology concepts are addressed. The potential pharmaceutical applications, like the enhancement in drug solubility, and the drug dissolution rate, which consequently leads to improved bioavailability and therapeutic efficacy, are also highlighted. This study briefly reviews different strategies for enhancing the solubility of poorly soluble drugs with a special emphasis on co-crystal formation, including solvent-based and solvent-free methods of production. [ABSTRACT FROM AUTHOR]

Background: The current challenge in drug development lies in addressing the physicochemical issues that lead to low drug effectiveness. Solubility, a crucial physicochemical parameter, greatly influences various biopharmaceutical aspects of a drug, including dissolution rate, absorption, and bioavailability. Amorphous solid dispersion (ASD) has emerged as a widely explored approach to enhance drug solubility. Objective: The objective of this review is to discuss and summarize the development of polyvinylpyrrolidone (PVP)-based amorphous solid dispersion in improving the physicochemical properties of drugs, with a focus on the use of PVP as a novel approach. Methodology: This review was conducted by examining relevant journals obtained from databases such as Scopus, PubMed, and Google Scholar, since 2018. The inclusion and exclusion criteria were applied to select suitable articles. Results: This study demonstrated the versatility and efficacy of PVP in enhancing the solubility and bioavailability of poorly soluble drugs. Diverse preparation methods, including solvent evaporation, melt quenching, electrospinning, coprecipitation, and ball milling are discussed for the production of ASDs with tailored characteristics. Conclusion: PVP-based ASDs could offer significant advantages in the formulation strategies, stability, and performance of poorly soluble drugs to enhance their overall bioavailability. The diverse methodologies and findings presented in this review will pave the way for further advancements in the development of effective and tailored amorphous solid dispersions. [ABSTRACT FROM AUTHOR]

[Display omitted] High dissolution of anticancer drugs directly adsorbed onto porous carriers is indispensable for the development of drug delivery systems with high bioavailability. We report direct adsorption/loading of the anticancer drug letrozole (LTZ) onto the clinoptilolite (CLI) zeolite after the surface activation. In vitro LTZ dissolution from the CLI zeolites reached 95 % after 23 h in an acidic medium, being faster than the dissolution of the pure LTZ molecules. Fast dissolution occurs due to uniform exposure of the LTZ onto the external surface of the CLI zeolites, being accessible to the solvent for dissolution. On the other hand, the LTZ molecules were hidden in the bulk phase, giving a slow dissolution rate. Small positive value of the CLI/LTZ adsorption energy of 0.06 eV suggests that the release process is favourable in aqueous media. The main merit of the CLI/LTZ system is its quick onset of action and high bioavailability. This work demonstrates a possibility of enhancement of the dissolution of poorly soluble LTZ from the CLI zeolite, being promising for the further development of drug delivery systems. [ABSTRACT FROM AUTHOR]

Pharmaceutical co-crystals have gained significant attention in recent years as a promising green and sustainable method for poorly soluble drugs to improve their solubility, stability, and bioavailability. In the drug development research field, it is an extremely useful technique as it does not require a large number of synthetic steps as well a minimum amount of solvent is utilized or sometimes without solvent. This review presents a comprehensive investigation into the design, synthesis, characterization, and evaluation of pharmaceutical co-crystals. The study focuses on exploring different strategies for co-crystal formation, including co-grinding, solvent evaporation, and liquid-assisted grinding. Various characterization techniques such as SCXRD, PXRD, FTIR, and DSC were employed to confirm the formation and structural features of the co-crystals. The article also highlights the significance of understanding the intermolecular interactions within co-crystals and their influence on physicochemical properties. Furthermore, the article discusses the potential applications of pharmaceutical co-crystals in enhancing drug solubility, dissolution rate, and oral bioavailability, leading to improved therapeutic efficacy. Overall, this review provides valuable insights into the design and development of pharmaceutical co-crystals, offering a promising avenue for overcoming the difficulties brought on by poorly soluble drugs. [ABSTRACT FROM AUTHOR]

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A series of triazinethiones was successfully synthesized through cycloaddition reaction between guanidine hydrochloride with isothiocyanate intermediates and further analyzed through in silico analysis employing molecular docking simulations and ADMET prediction to investigate their potential anti-inflammatory activity. The ADMET profile of the synthesized triazinethione derivatives were found to possess favorable drug-like properties with good solubility (0.58–1.89 mg/mL) and oral bioavailability (0.55). The molecular docking analysis showed that among the synthesized triazinethione, 6-amino-4-(4-nitrophenyl)-1,3,5-triazine-2(1H)-thione exhibited a higher binding affinity with anti-inflammatory related enzymes, COX-2 (–7.8 kcal/mol) and iNOS (–6.1 kcal/mol) in comparison to standard drugs of salicylic acid (–6.2 kcal/mol) and Imidazopyridines (–5.9 kcal/mol), respectively owing to the hydrogen bond and hydrophobic interaction. The findings imply that triazinethione derivatives could make excellent possibilities for the development of new anti-inflammatory drugs. [ABSTRACT FROM AUTHOR]

Biphasic in vitro dissolution testing is an attractive approach to reflect on the interplay between drug dissolution and absorption for predicting the bioperformance of drug products. The purpose of this study was to investigate the in vivo relevance of a biphasic dissolution test for the immediate release (IR) formulations of a Biopharmaceutics Classification System (BCS) Class II drug, lamotrigine (LTG). The biphasic dissolution test was performed using USP apparatus II with the dual paddle modification. A level A in vitro-in vivo correlation (IVIVC) was constructed between the in vitro partition into the octanol and absorption data of the reference product. A good relation between in vitro data and absorption was obtained (r2 = 0.881). The one-compartment open model was introduced to predict the human plasma profiles of the test product. The generic product was found to be bioequivalent to the original product in terms of 80–125% bioequivalence (BE) criteria (85.9–107% for the area under the plasma concentration curve (AUC) and 82.7–97.6% for the peak plasma concentration (Cmax) with a 90% confidence interval (CI)). Overall, it was revealed that the biphasic dissolution test offers a promising ability to estimate the in vivo performance of IR formulations of LTG, providing considerable time and cost savings in the development of generic drug products. [ABSTRACT FROM AUTHOR]

Bioavailability is a prerequisite for drug activity. In vivo bioavailability (intestinal permeability), linked to drug substance solubility and drug product dissolution, became the basis of Gordon L. Amidon's Biopharmaceutical Classification System. One method of improving the drug substance's bioavailability is to modify its structure chemically, leading to increased lipophilicity and the ability to penetrate the phospholipid bilayer of the cell membrane. These modifications, known as prodrug strategies, involve derivatizing the drug substance by introducing substituents that reduce the hydrophilicity of the molecule. The present mini-review outlines the examples of Christopher McGuigan's prodrug strategies used to obtain antiviral nucleosides with enhanced bioavailability and activity. These strategies primarily involve forming and optimizing the structure of esters and amino acid esters, phosphoramidates, octadecyl phosphates, and bis-pivaloxymethyl phosphates. The review discusses the optimization of the phosphoramidate prodrug moiety of the SARS-CoV-2 antiviral nucleoside remdesivir in detail. It presents the resulting improvement in bioavailability and antiviral activity. Moreover, it focuses on the modern prodrug strategy as one of the major recent advances in drug substance development. This strategy effectively optimized physicochemical properties and improved the functional activity of the existing drug substances and drug substance candidates for the first time. [ABSTRACT FROM AUTHOR]

[Display omitted] • The interindividual and interoccasion variability of drug disposition parameters is often neglected when simulating bioequivalence trials. • The paper describes a novel approach to address this issue by joining biorelevant dissolution tests, semi-mechanistic description of the gastrointestinal passage, and the population-based description of drug disposition. • The model allowed simulating the plasma concentrations for the originator and several candidate formulations, and the VBE results were comparable with the outcomes of the true bioequivalence trial in healthy volunteers. Virtual bioequivalence trial (VBE) simulations based on (semi)mechanistic in vitro-in vivo (IVIV) modeling have gained a huge interest in the pharmaceutical industry. Sophisticated commercially available software allows modeling variable drug fates in the gastrointestinal tract (GIT). Surprisingly, the between-subject and inter-occasion variability (IOV) of the distribution volumes and clearances are ignored or simplified, despite substantially contributing to varied plasma drug concentrations. The paper describes a novel approach for IVIV-based VBE by using population pharmacokinetics (popPK). The data from two bioequivalence trials with a poorly soluble BCS class II drug were analyzed retrospectively. In the first trial, the test drug product (biobatch 1) did not meet the bioequivalence criteria, but after a reformulation, the second trial succeeded (biobatch 2). The popPK model was developed in the Monolix software (Lixoft SAS, Simulation Plus) based on the originator's plasma concentrations. The modified Noyes-Whitney model was fitted to the results of discriminative biorelevant dissolution tests of the two biobatches and seven other reformulations. Then, the IVIV model was constructed by joining the popPK model with fixed drug disposition parameters, the drug dissolution model, and mechanistic approximation of the GIT transit. It was used to simulate the drug concentrations at different IOV levels of the primary pharmacokinetic parameters and perform the VBE. Estimated VBE success rates for both biobatches well reflected the outcomes of the bioequivalence trials. The predicted 90% confidence intervals for the area under the time-concentration curves were comparable with the observed values, and the 10% IOV allowed the closest approximation to the clinical results. Simulations confirmed that a significantly lower maximum drug concentration for biobatch 1 was responsible for the first clinical trial's failure. In conclusion, the proposed workflow might aid formulation screening in generic drug development. [ABSTRACT FROM AUTHOR]

The development of effective drug formulations and delivery systems for newly developed or marketed drug molecules remains a significant challenge. These drugs can exhibit polymorphic conversion, poor bioavailability, and systemic toxicity, and can be difficult to formulate with traditional organic solvents due to acute toxicity. Ionic liquids (ILs) are recognized as solvents that can improve the pharmacokinetic and pharmacodynamic properties of drugs. ILs can address the operational/functional challenges associated with traditional organic solvents. However, many ILs are non-biodegradable and inherently toxic, which is the most significant challenge in developing IL-based drug formulations and delivery systems. Biocompatible ILs comprising biocompatible cations and anions mainly derived from bio-renewable sources are considered a green alternative to both conventional ILs and organic/inorganic solvents. This review covers the technologies and strategies developed to design biocompatible ILs, focusing on the design of biocompatible IL-based drug formulations and delivery systems, and discusses the advantages of these ILs in pharmaceutical and biomedical applications. Furthermore, this review will provide guidance on transitioning to biocompatible ILs rather than commonly used toxic ILs and organic solvents in fields ranging from chemical synthesis to pharmaceutics. [ABSTRACT FROM AUTHOR]

Innumerable problems are encountered while formulating a drug of poor water solubility into a formulation with good bioavailability. A couple of decades ago, the reason behind failures in drug development was due to poor biopharmaceutical properties such as poor water solubility of the drugs molecules. The process of new drug development can come to a standstill if the drug candidate has poor water solubility or if it is completely insoluble in water. Due to poor solubility of drugs in water, many marketed products need to be reformulated as the formulation cannot avail the desired amount of drug to the site of action. The drugs can provide relief, but the diuretics are poorly soluble in nature. So, formulating them is a tedious and difficult task. So, before formulation their solubility should be enhanced in order to increase drug availability and bioavailability simultaneously. The present research work aims to enhancing the solubility of the drug to multiple folds. Solid dispersion particularly aims at enhancing the solubility of poorly water-soluble drugs by the use of solid solubilises. A combination of solubilises can be used to enhance the solubility of the drug leading to reduction in individual concentrations of solubilises and effective enhancement of solubility of the drug. In the present study, poorly water-soluble drug, Torsemide, was the drug of choice. It was incorporated into solid dispersion using random combination of several solubilizes. The solubilizes were dissolved in water and then drug was added, a clear yellow solution was formed. The excess water was evaporated from this solution and solid dispersion was obtained which was later dried completely, pulverized and packed [ABSTRACT FROM AUTHOR]

Oral delivery has become the route of choice among all other types of drug administrations. However, typical chronic disease drugs are often poorly water-soluble, have low dissolution rates, and undergo first-pass metabolism, ultimately leading to low bioavailability and lack of efficacy. The lipid-based formulation offers tremendous benefits of using versatile excipients and has great compatibility with all types of dosage forms. Self-microemulsifying drug delivery system (SMEDDS) promotes drug self-emulsification in a combination of oil, surfactant, and co-surfactant, thereby facilitating better drug solubility and absorption. The feasible preparation of SMEDDS creates a promising strategy to improve the drawbacks of lipophilic drugs administered orally. Selecting a decent mixing among these components is, therefore, of importance for successful SMEDDS. Quality by Design (QbD) brings a systematic approach to drug development, and it offers promise to significantly improve the manufacturing quality performance of SMEDDS. Furthermore, it could be benefited efficiently by conducting pre-formulation studies integrated with the statistical design of experiment (DoE). In this review, we highlight the recent findings for the development of microemulsions and SMEDDS by using DoE methods to optimize the formulations for drugs in different excipients with controllable ratios. A brief overview of DoE concepts is discussed, along with its technical benefits in improving SMEDDS formulations. [ABSTRACT FROM AUTHOR]

Scaffold development is a nascent field in drug development. The scaffolds mimic the innate microenvironment of the body. The goal of this study was to formulate a biocompatible and biodegradable scaffold, loaded with an analgesic drug, aceclofenac (Ace). The bioscaffold is aimed to have optimum mechanical strength and rheology, with drug released in a sustained manner. It was prepared via chemical cross-linking method: a chitosan (CS) solution was prepared and loaded with Ace ; gelatin (GEL) was added and the mixture was cross-linked to get a hydrogel. 20 formulations were prepared to optimize different parameters including the stirring speed, drug injection rate and crosslinker volume. The optimal formulation was selected based on the viscosity, drug solubility, homogeneity, porosity and swelling index. A very high porosity and swelling index were attained. In vitro release data showed sustained drug delivery, with effective release at physiological and slightly acidic pH. SEM analysis revealed a homogeneous microstructure with highly interconnected pores within an extended polymer matrix. FT-IR spectra confirmed the absence of polymer-drug interactions, XRD provided evidences for efficient drug entrapment within the scaffold. Rheological analysis corroborated the scaffold injectability. Mathematical models were applied to in-vitro data, and the best fit was attained with Korsmeyer-Peppas. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Gastroretentive drug delivery systems (GRDDS) are modified-release dosage forms designed to prolong their residence time in the upper gastrointestinal tract, where some drugs are preferentially absorbed, and increase the drug bioavailability. This work aimed the development of a novel GRDDS containing 60 mg of sildenafil citrate, and the evaluation of the feasibility of the proposed formulation for use in the treatment of pulmonary arterial hypertension (PAH), for once a day administration, by using in silico pharmacokinetic (PK) modeling and simulations using GastroPlusTM. The Model-Informed Drug Development (MIDD) approach was used in formulation design and pharmacokinetic exposure prospecting. A 22 factorial design with a central point was used for optimization of the formulation, which was produced by direct compression and characterized by some tests, including buoyancy test, assay, impurities, and in vitro dissolution. A compartmental PK model was built using the GatroPlusTM software for virtual bioequivalence of the proposed formulations in comparison with the defined target release profile provided by an immediate release (IR) tablet formulation containing 20 mg of sildenafil administered three times a day (TID). The results of the factorial design showed a direct correlation between the dissolution rate and the amount of hydroxypropyl methyl cellulose (HPMC) in the formulations. By comparing the PK parameters predicted by the virtual bioequivalence, the formulations F1, F2, F3 and F5 failed on bioequivalence. The F4 showed bioequivalence to the reference and was considered the viable formulation to substitute the IR. Thus, GRDDS could be a promising alternative for controlling the release of drugs with a pH-dependent solubility and narrow absorption window, specifically in the gastric environment, and an interesting way to reduce dose frequency and increase the drug bioavailability. The MIDD approach increases the level of information about the pharmaceutical product and guide the drug development for more assertive ways. [ABSTRACT FROM AUTHOR]

Most recently discovered active pharmaceutical molecules and market-approved medicines are poorly soluble in water, resulting in limited drug bioavailability and therapeutic effectiveness. The application of coformers in a multicomponent crystal method is one possible strategy to modulate a drug's solubility. A multicomponent crystal is a solid phase formed when several molecules of different substances crystallize in a crystal lattice with a certain stoichiometric ratio. The goal of this review paper is to comprehensively describe the application of coformers in the formation of multicomponent crystals as solutions for pharmaceutically active ingredients with limited solubility. Owing to their benefits including improved physicochemical profile of pharmaceutically active ingredients, multicomponent crystal methods are predicted to become increasingly prevalent in the development of active drug ingredients in the future [ABSTRACT FROM AUTHOR]

Biopharmaceutical classification system (BCS) is an advanced tool used for classifying medicines based on dissolution, water solubility, and intestinal permeability, which affect the absorption of active pharmaceutical ingredients (API) from immediate-release solid oral forms. It is useful to the formulation researchers to develop novel dosage forms based on modernistic rather than experimental approaches. The current review focuses on the fundamentals, objectives, guidance of BCS, characteristics of BCS drugs, their importance and applications of BCS. This review explains the challenges in drug development in terms of solubility and in vivo disposition. In the current review, new strategies for improving BCS II drug solubility as well as biopharmaceutical drug disposition properties which are utilized throughout the early stages of drug development and commercialization are mainly discussed. [ABSTRACT FROM AUTHOR]

[Display omitted] Long-acting parenteral drug products are a popular choice for therapeutic areas requiring long term treatment. These products range from dispersed systems such as drug suspensions and polymeric microspheres to in situ forming polymeric implants. The lack of reliable drug release testing methods for these drug products not only impedes the development of new drug products but also affects generic drug development. Current release methods suffer from a range of problems such as high variability, poor reproducibility, poor discriminatory ability, lack of depot-like structure formation (that could mimic the in vivo situation). Moreover, shorter duration (less than a week) of release renders them unsuitable for in vitro-in vivo correlations (IVIVCs). To overcome these issues, novel adapters were developed for both USP-type-II & IV apparatus. These adapters were validated and assessed using the long-acting injectable (LAI) suspension drug product Depo Provera 150® as well as its Q1/Q2 equivalents. For USP-type-IV apparatus, two open adapter designs (conical and ellipsoidal shaped cavity with volume capacities of 50 µl and 1 ml, respectively) were developed. A closed conical adapter design with a volume capacity of 0.05 ml was developed for USP apparatus type-II. All three novel adapter designs effectively retained the suspensions, achieved release durations of 3–6 weeks with good reproducibility, minimal variability (RSD≤5%) and had good discriminatory ability. Based on this, the adapter-based dissolution methods were deemed suitable for IVIVC development of long-acting injectables. A successful Level A IVIVC was developed for Depo SubQ Provera 104® and its Q1Q2 equivalents using USP apparatus type IV with a conical adapter design. The closed adapter design for apparatus type-II was also investigated for suitability with risperidone in situ forming implants. The adapter was able to securely retain and maintain the shape of the in situ forming implants and resulted in release profiles of up to one month with good discriminatory ability and low standard error (RSD≤5%). These novel adapters hold promise of wide use for in vitro release testing of different long-acting parenteral drug products. [ABSTRACT FROM AUTHOR]

Objectives: Baclofen is a skeletal muscle relaxant with a short half-life and a narrow absorption window in the upper part of the gastrointestinal tract, and this study aims to formulate a sustained-release tablet of baclofen and 3D printing of gastro-floating device and study the effect of various polymers and device design on the release profile of baclofen. Method: Firstly, four formulas were produced through the hot-melt extrusion and direct compression of the extrudate to produce 30 mg baclofen tablets, then four gastro-floating devices (A, B, C, and D) were designed with two air pockets to enable the floating of the device and have drug-releasing windows with total surface area 4, 10, 20, and 40 mm2 respectively, for drug release. 3D printing of the devices was done by an FDM printer and the tablets were inserted into each device and test it for drug release. Results: Decreasing the surface area of the drug releasing windows revealed a significant reduction in the dissolution of baclofen irrespective of the type of polymers and useful for sustained release formulation but may be associated with lag time. Devices with one and two releasing windows (Device B and C respectively) sometimes revealed similar dissolution profiles and this related to the position of the window regarding the surface of the dissolution media. Device D with four windows and a 40 mm2 surface area was found to produce more reliable results. F3 which contains Eudragit RS-100 as the main polymer showed sustained release in device D where the complete dissolution of the drug occurred in 12 hours, and the gastro-floating device remained floating all the time and was assayed for drug content, FT-IR, and DSC study. Conclusion: Hot-melt extrusion was successfully employed to produce sustained release tablets of baclofen. FDM 3D printers are considered a potential tool to produce gastro-floating devices with the required design and release profile. [ABSTRACT FROM AUTHOR]

It is estimated that 90% of new drugs in development are classified as poorly soluble. Many drug molecules are lipophilic or hydrophobic in nature and thus they usually show low bioavailability, poor absorption properties, low permeation as well as inability to reach an effective therapeutic concentration in blood. To overcome this problem, nano micelles are the breakthrough drug delivery system in which a lipophilic drug can be incorporated into polymeric micelles or surfactant micelles that can provide high solubility as well as high bioavailability. Since Micelles have an inner lipophilic core and outer hydrophilic shell as well as the inner lipophilic core provides space for incorporation of the lipophilic drug, it enhances the permeability of the lipophilic drug even at depth and also at the target site. The present review outline various applications of nanomicelles, their advantages as well as limitations, methods of preparations, and various approaches for applications of nanomicelles. [ABSTRACT FROM AUTHOR]

The most favored approach for drug administration is the oral route. Several anticancer drugs come under this category and mostly lack solubility and oral bioavailability, which are the most common causes of inadequate clinical efficiency. Enhancing oral absorption of anticancer drugs with low aqueous solubility and drug impermeability is currently an effective area of research. Many scientists have looked into pharmaceutical cocrystals as a way to improve the physicochemical properties of several anticancer drugs. Benefits of pharmaceutical cocrystals over other solid forms may include improved solubility, bioavailability, and a reduced susceptibility for phase transition. Cocrystal strategy also stands as a green synthesis tool by using very limited organic solvents during its formulation. Having so many advantages, to date, the reported cocrystals and drug–drug cocrystals of anticancer drugs are limited. Here we review the pharmaceutical cocrystals and drug–drug cocrystals of the anticancer drugs reported in the last decade and their future in imaging, and also shed light on the opportunities and challenges for the development of anticancer drug cocrystals. [ABSTRACT FROM AUTHOR]

The low solubility and bioavailability of aqueous insoluble drugs are critical challenges in the field of pharmaceuticals that need to be overcome. Nanocrystal technology, a novel pharmacological route to address the poor aqueous solubility problem of many poorly soluble drugs, has recently demonstrated great potential for industrial applications and developments. This review focuses on today's preparation technologies, containing top-down, bottom-up, and combinative technology. Among them, the highlighted combinative technology can improve the efficiency of particle size reduction and overcome the shortcomings of a single technology. Then, the characterization methods of nanocrystal production are presented in terms of particle size, morphology, structural state, and surface property. After that, we introduced performance evaluations on the stability, safety, and the in vitro/in vivo dissolution of drug nanocrystals. Finally, the applications and prospects of nanocrystals in drug development are presented. This review may provide some references for the further development and optimization of poorly soluble drug nanocrystals. [ABSTRACT FROM AUTHOR]

Nowadays, supercritical CO2(SC-CO2) is known as a promising alternative for challengeable organic solvents in the pharmaceutical industry. The mathematical prediction and validation of drug solubility through SC-CO2 system using novel artificial intelligence (AI) approach has been considered as an interesting method. This work aims to evaluate the solubility of tamoxifen as a chemotherapeutic drug inside the SC-CO2 via the machine learning (ML) technique. This research employs and boosts three distinct models utilizing Adaboost methods. These models include K-nearest Neighbor (KNN), Theil-Sen Regression (TSR), and Gaussian Process (GPR). Two inputs, pressure and temperature, are considered to analyze the available data. Furthermore, the output is Y, which is solubility. As a result, ADA-KNN, ADA-GPR, and ADA-TSR show an R2 of 0.996, 0.967, 0.883, respectively, based on the analysis results. Additionally, with MAE metric, they had error rates of 1.98 × 10−6, 1.33 × 10−6, and 2.33 × 10−6, respectively. A model called ADA-KNN was selected as the best model and employed to obtain the optimum values, which can be represented as a vector: (X1 = 329, X2 = 318.0, Y = 6.004 × 10−5) according to the mentioned metrics and other visual analysis. [ABSTRACT FROM AUTHOR]

Intensive research subjected to the improvement of solubility and bioavailability of certain drugs has popularized the formation of cocrystals, wherein the desired drug is non-ionically bonded to a coformer by means of weak bonds. This paper addresses how crystal engineering of two compatible drug components can enhance the physicochemical and therapeutic properties of either or both of the drugs, resulting in drug-drug cocrystals, with pertinent examples. The paper also discusses the continuous screening processes which are replacing the traditional methods of crystallization due to numerous benefits to the producer as well as the products. Although faced with certain regulatory and scale-up constraints, cocrystals provide immense opportunities to the field of novel drug development. [Display omitted] • Various screening, manufacturing, and solid-state characterization methods concerning cocrystals have been discussed. • A comparative study between older and newer methods of manufacturing pertaining to ease of scale-up has been done. • Physicochemical and therapeutic advantages of drug-drug cocrystals over pure crystals have been elaborated with examples. • Cocrystals that have made their way to the market, in spite of the mentioned regulatory constraints, have been discussed. [ABSTRACT FROM AUTHOR]

Over the past few decades, researchers and companies have been trying to develop novel drug delivery systems to ensure safety, efficacy, compliance, and patient acceptability. Nowadays drug discovery and development are expensive, complex, and time-consuming processes, but trends are moving toward novel drug delivery systems. This delivery system helps to achieve drug response by local and systemic action through different routes. This novel approach of preparing orodispersible films (ODFs) provides benefits to paediatric, geriatric, and bedridden patients. This review paper aims to provide details on the preparation, characterization, and evaluation of ODFs; it also aims to focus on the positive and negative factors that affect film formulation and give an insight into potential drug candidates and polymers for use in ODFs. ODFs are effective, safe, and have good bioavailability as compared to fast-disintegrating tablets. The novel approach has various advantages because it provides instant effects in emergency situations and in schizophrenic and dysphasic patients without the need for taking water, the films disintegrating within a few seconds in the oral cavity. The solvent casting method is the most frequently used technique to develop ODFs, using film-forming polymers, which have a fast disintegration time, improved drug dissolution, and better drug contents. [ABSTRACT FROM AUTHOR]

• Using three methods and different conformations of DIP to predict its cocrystals behavior. • Analyzed the differences between predicted cocrystals behavior and experimental results using different conformations. • When predicting cocrystal behavior using MC and MEP methods, it is necessary to consider the molecular conformation, as different conformations can significantly affect the prediction results. Drug development necessitates substantial investments in both human and material resources. In the advanced stages of development, significant solubility challenges frequently emerge, critically influencing a drug's applicability and efficacy. Crystal engineering, particularly through the application of cocrystal technology, presents a novel strategy to address these solubility issues without compromising the drug's effectiveness. However, the success rate of cocrystals formation remains relatively low. This article evaluates the impact of widely used virtual cocrystal screening methods on prediction outcomes, especially in the context of conformational diversity. The study describes the effects of eight dipyridamole (DIP) conformations and 130 cocrystal formers (CCFs) using molecular complementarity and molecular electrostatic potential methods, while the hydrogen bond propensity method did not account for conformations variations. Findings indicate that different DIP conformations lead to variable prediction outcomes in virtual cocrystal screening. Thus, it is crucial consider the conformational states of APIs and CCFs in virtual screenings to enhance prediction accuracy. By comparing virtual screening results with experimental results, this study demonstrated that incorporating conformational considerations can improve cocrystal success rates, minimize experimental workload, and contribute to energy-conservation and emission-reduction. Additionally, this research provides the true positives and true negatives data of DIP's cocrystal, laying the groundwork for further studies. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Traditionally, developing inhaled drug formulations relied on trial and error, yet recent technological advancements have deepened the understanding of 'inhalation biopharmaceutics' i.e. the processes that occur to influence the rate and extent of drug exposure in the lungs. This knowledge has led to the development of new in vitro models that predict the in vivo behavior of drugs, facilitating the enhancement of existing formulation and the development of novel ones. Our prior research examined how simulated lung fluid (SLF) affects the solubility of inhaled drugs. Building on this, we aimed to explore drug dissolution and permeability in lung mucosa models containing mucus. Thus, the permeation of four active pharmaceutical ingredients (APIs), salbutamol sulphate (SS), tiotropium bromide (TioBr), formoterol fumarate (FF) and budesonide (BUD), was assayed in porcine mucus covered Calu-3 cell layers, cultivated at an air liquid interface (ALI) or submerged in a liquid covered (LC) culture system. Further analysis on BUD and FF involved their transport in a mucus-covered PAMPA system. Finally, their dissolution post-aerosolization from Symbicort® was compared using 'simple' Transwell and complex DissolvIt® apparatuses, alone or in presence of porcine mucus or polymer-lipid mucus simulant. The presence of porcine mucus impacted both permeability and dissolution of inhaled drugs. For instance, permeability of SS was reduced by a factor of ten in the Calu-3 ALI model while the permeability of BUD was reduced by factor of two in LC and ALI setups. The comparison of dissolution methodologies indicated that drug dissolution performance was highly dependent on the setup, observing decreased release efficiency and higher variability in Transwell system compared to DissolvIt®. Overall, results demonstrate that relatively simple methodologies can be used to discriminate between formulations in early phase drug product development. However, for more advanced stages complex methods are required. Crucially, it was clear that the impact of mucus and selection of its composition in in vitro testing of dissolution and permeability should not be neglected when developing drugs and formulations intended for inhalation. [ABSTRACT FROM AUTHOR]

• Seamless solubility understanding requires discovery-development collaboration. • Gold standard methods in drug development map solubility of drug candidates. • Drug development solubility informs developability and drug product strategies. • Evolving drug discovery solubility assays incorporate development practices. • Drug discovery solubility assays benefit discovery-development learning cycles. Solubility is a key physicochemical property for the success of any drug candidate. Although the methods used and their rationales for determining solubility are subject to project needs and stages along the drug discovery–drug development pipeline, an artificial boundary can exist at the discovery–development interface. This boundary results in less effective solubility knowledge sharing and data integration among scientists in both drug discovery and drug development. Herein, we present a refreshed perspective on solubility. Solubility experimentation is not a one-size-fits-all measurement; instead, we stress the importance of constructing a seamless solubility understanding of a molecule as it progresses from a new chemical entity into a drug product. [ABSTRACT FROM AUTHOR]

This work aims to evaluate the ability of biorelevant dissolution media to simulate the bioavailability of efavirenz tablets, establish an in vitro–in vivo relationship (IVIVR) based on in vivo data using GastroPlus® and simulate formulation changes using DDDPlus™. Solubility and drug release profiles were conducted in SLS 0.5% and biorelevant media, such as FaSSIF, FeSSIF, FaSSIF-V2, and FeSSIF-V2. The efavirenz physicochemical properties were used to simulate the plasma concentration profile and compare the simulated pharmacokinetic parameters in fasted and fed states. An IVIVR was developed using Loo-Riegelman as the deconvolution method to estimate drug bioavailability. DDDPlus™ was used to perform virtual trials of formulations to evaluate whether formulations changes and the efavirenz particle size could influence the bioavailability. The drug dissolution displayed higher levels in the biorelevant media that simulated gut-fed state (FeSSIF and FeSSIF-V2). The absorption model successfully predicted the efavirenz pharmacokinetics, and FeSSIF-V2 was chosen as the predictive dissolution media, while an IVIVR was established using the Loo-Riegelman deconvolution method. The present work provides valuable information about efavirenz solubility and kinetics in the gastrointestinal tract, allowing an IVIVR to support future formulation changes. This understanding is essential for rational science-driven formulation development. At least, this study also showed the validity and applicability of in vitro and in silico tools in the regulatory scenario helping on drug development. [ABSTRACT FROM AUTHOR]

Most of the promising drugs in development channels are poorly water-soluble drugs which limit formulation approaches, clinical application because of their low dissolution and bioavailability. And the major current challenges of the pharmaceutical industry are apropos strategies that improve the water solubility of drugs. Solid dispersion has been considered one of the major evolutions in overcoming these issues with several successfully marketed products. Though solid dispersion has been outlined as an efficient drug delivery system, the design of specific dosage forms for pharmaceutical therapy is necessary to improve the solubility and bioavailability of poorly water-soluble drugs. Solid dispersion can be prepared by several methods such as solvent evaporation, melting, and supercritical fluid technology. This review intends to provide an updated overview of the recent trends over the past few years in solid dispersion preparation techniques and polymer used. Along with the various pharmaceutical strategies and future visions for the solubilization of poorly water-soluble drugs [ABSTRACT FROM AUTHOR]

[Display omitted] The aim of the current work was to investigate the key factors that govern the success/failure of an ethanol-based solubility-enabling oral drug formulation, including the effects of the ethanol on the solubility of the drug, the permeability across the intestinal membrane, the drug's dissolution in the aqueous milieu of the gastrointestinal tract (GIT), and the resulting solubility-permeability interplay. The concentration-dependent effects of ethanol-based vehicles on the solubility, the in-vitro Caco-2 permeability, the in-vivo rat permeability, and the biorelevant dissolution of the BCS class II antiepileptic drug carbamazepine were studied, and a predictive model describing the solubility-permeability relationship was developed. Significant concentration-dependent solubility increase of CBZ was obtained with increasing ethanol levels, that was accompanied by permeability decrease, both in Caco-2 and in rat perfusion studies, demonstrating a tradeoff between the increased solubility afforded by the ethanol and a concomitant permeability decrease. When ethanol absorption was accounted for, an excellent agreement was achieved between the predicted permeability and the experimental data. Biorelevant dissolution studies revealed that minimal ethanol levels of 30 % and 50 % were needed to fully dissolve 1 and 5 mg CBZ dose respectively, with no drug precipitation. In conclusion, key factors to be accounted for when developing ethanol-based formulation include the drug's solubility, permeability, the solubility-permeability interplay, and the drug dose intended to be delivered. Only the minimal amount of ethanol sufficient to solubilize the drug dose throughout the GIT should be used, and not more than that, to avoid unnecessarily permeability loss, and to maximize overall drug absorption. [ABSTRACT FROM AUTHOR]

This study aims to understand the absorption patterns of three different kinds of inhaled formulations via in silico modeling using budesonide (BUD) as a model drug. The formulations investigated in this study are: (i) commercially available micronized BUD mixed with lactose (BUD-PT), (ii) BUD nanocrystal suspension (BUD-NC), (iii) BUD nanocrystals embedded hyaluronic acid microparticles (BUD-NEM). The deposition patterns of the three inhaled formulations in the rats' lungs were determined in vivo and in silico predicted, which were used as inputs in GastroPlus TM software to predict drug absorption following aerosolization of the tested formulations. BUD pharmacokinetics, estimated based on intravenous data in rats, was used to establish a drug-specific in silico absorption model. The BUD-specific in silico model revealed that drug pulmonary solubility and absorption rate constant were the key factors affecting pulmonary absorption of BUD-NC and BUD-NEM, respectively. In the case of BUD-PT, the in silico model revealed significant gastrointestinal absorption of BUD, which could be overlooked by traditional in vivo experimental observation. This study demonstrated that in vitro-in vivo-in silico approach was able to identify the key factors that influence the absorption of different inhaled formulations, which may facilitate the development of orally inhaled formulations with different drug release/absorption rates. [ABSTRACT FROM AUTHOR]

This workshop report summarizes the proceedings of Day 1 of a three-day workshop on "Current State and Future Expectations of Translational Modeling Strategies to Support Drug Product Development, Manufacturing Changes and Controls". Physiologically based biopharmaceutics models (PBBM) are tools which enable the drug product quality attributes to be linked to the in vivo performance. These tools rely on key quality inputs in order to provide reliable predictions. After introducing the objectives of the workshop and the expectations from the breakout sessions, Day 1 of the workshop focused on the best practices and challenges in measuring in vitro inputs needed for modeling, such as the drug solubility, the dissolution rate of the drug product, potential precipitation of the drug and drug permeability. This paper reports the podium presentations and summarizes breakout session discussions related to A) the best strategies for determining solubility, supersaturation and critical supersaturation; B) the best strategies for the development of biopredictive (clinically relevant) dissolution methods; C) the challenges associated with describing gastro-intestinal systems parameters such as mucus, liquid volume and motility; and D) the challenges with translating biopharmaceutical measures of drug permeability along the gastrointestinal tract to a meaningful model parameter. [ABSTRACT FROM AUTHOR]

Increasing numbers of poorly water soluble drugs in development has intensified need for bio-enabling formulations including Lipid-Based Formulations (LBF) and Solid Dispersions (SD). Resultantly, a data-driven approach is required to increase formulation development efficiency. This review provides a retrospective analysis of molecular and biopharmaceutical properties of drugs commercialised as LBFs or SDs. A comprehensive stepwise statistical analysis of LBF and SD drug properties was conducted and compared to drugs not commercialised via either technology (Others), aiming to identify key predictors of successful formulation development. This review demonstrates LBF and SD drugs differ significantly in molecular weight, polar surface area, rotatable bonds and hydrogen bond acceptor count. Meanwhile, LBF and SD drugs display significantly different aqueous solubility, lipophilicity, size, molecular flexibility, hydrogen bonding capacity and rule-of-5 violations versus Others. LBF and SDs were 3 and 5 times more likely to display >1 rule-of-5 violation versus Others, over 55% of LBF drugs exceeded the reported melting point guide of <150 °C, while 24% of SD drugs contained >10 Hydrogen Bond Acceptors. Overall, by focusing on successfully commercialised drugs, this review provides improved understanding of links between drug properties and successful SD/LBF approaches, providing a framework for guiding pharmaceutical development on formulation approaches. [ABSTRACT FROM AUTHOR]

In the present research, newly developed complex with sodium caprylate was investigated for solubility and dissolution enhancement of eluxadoline. Complexes were prepared in different ratios by solvent evaporation method and characterised solubility study, Infrared spectroscopy (IR), Diffrential scanning calorimetry (DSC), X-Ray Diffraction (XRD), drug content analysis and in vitro drug release. The solubility and dissolution rate revealed most suitable ratio of Eluxadoline and sodium caprylate (1:4). The IR, DSC and X-RD data also confirmed the results. It was concluded that complex prepared with (1:4 drug:sodium caprylate ratio) using solvent evaporation method showed significant improvement in solubility and drug dissolution. [ABSTRACT FROM AUTHOR]

Simulated human intestinal media, have proved to be a useful biopharmaceutics tool as a dissolution media for predicting in vivo dissolution and pharmacokinetic profile in humans. During drug product development preclinical animal models are also required to assess drug product performance, and there is a need to develop species specific intestinal media to similarly predict in vivo pharmacokinetic profiles in each preclinical model. Pigs, are increasingly being used in preclinical drug development, however to date there is a lack of quantitative information about the composition of porcine gastrointestinal (GI) fluids. As a result, a porcine biorelevant medium has not yet been developed, which is essential to improve interpretation and forecast of preclinical results using biorelevant in vitro dissolution studies. GI fluid samples, were collected from landrace pigs, and characterized. Fasted State Simulated Intestinal Fluid of pigs (FaSSIFp) was developed based on the physiological composition of the GI fluids in terms of pH, buffer capacity, osmolality, surface tension, as well as the bile salt, phospholipid and free fatty acid content. This study demonstrated that FaSSIFp was superior at predicting the solubility of the six model drugs in porcine intestinal fluids (PIF). A markedly high correlation (r2 0.98) was observed between the solubility obtained in PIF and FaSSIFp, whereas poor correlation (r2 0.12) was found for the solubility of the model drugs between human FaSSIF and PIF. This confirms that species specific biorelevant intestinal media are crucial to provide more accurate predictions of pharmacokinetic studies in preclinical models. Additionally, the availability of a species specific intestinal medium offers the potential to improve in vitro - in silico approaches to predict in vivo absorption and to reduce the overall number of animals needed in oral drug product development testing. [ABSTRACT FROM AUTHOR]

Excipients used in drug formulations at clinically safe levels have been considered to be pharmacologically inert; however, numerous studies have suggested that many solubilizing agents may modulate drug transporter activities and intestinal absorption. Here, the reported interactions between various solubilizing excipients and drug transporters are evaluated to consider various potential underlying mechanisms. This forms the basis for debate in the field in regard to whether or not the effects are based on "direct" interactions or "indirect" consequences arising from the role of the excipients. For example, an increase in apparent drug solubility can give rise to saturation of transporters according to Michaelis-Menten kinetics. This is also drawing the attention of regulatory agencies as they seek to understand the role of formulation additives. The continued application of excipients as a tool in solubility enhancement is crucial in the drug development process, creating a need for additional data to verify the proposed mechanism behind these changes. A literature review is provided here with some guidance on other factors that should be considered to delineate the effects that arise from direct physiological interactions or indirect effects. The results of such studies may aid the rational design of bioavailability-enhancing formulations. [ABSTRACT FROM AUTHOR]

Objectives: The Biopharmaceutics Classification System (BCS) categorizes active pharmaceutical ingredients according to their solubility and permeability properties, which are susceptible to matrix or formulation effects. The aim of this research was to evaluate the matrix effects of a hydroethanolic extract of calyces from Physalis peruviana L. (HEE) and its butanol fraction (BF), on the biopharmaceutics classification of their major compound, quercetin‐3‐O‐rutinoside (rutin, RU). Methods: Rutin was quantified by HPLC‐UV, and Caco‐2 cell monolayer transport studies were performed to obtain the apparent permeability values (Papp). Aqueous solubility was determined at pH 6.8 and 7.4. Key findings: The Papp values followed this order: BF > HEE > RU (1.77 ± 0.02 > 1.53 ± 0.07 > 0.90 ± 0.03 × 10−5 cm/s). The lowest solubility values followed this order: HEE > RU > BF (2.988 ± 0.07 > 0.205 ± 0.002 > 0.189 ± 0.005 mg/ml). Conclusions: According to these results, rutin could be classified as BCS classes III (high solubility/low permeability) and IV (low solubility/low permeability), depending on the plant matrix. Further work needs to be done in order to establish how apply the BCS for research and development of new botanical drugs or for bioequivalence purposes. [ABSTRACT FROM AUTHOR]

Biopharmaceutics Classification System (BCS) has gained broad acceptance in promoting the development of human drugs. To date, the applicability of existing human BCS criteria has not been evaluated in chickens. The objective of this study was to discuss the feasibility of BCS extrapolation between species and establish a preliminary chicken BCS by classifying seven veterinary commonly used drugs including metronidazole, amoxicillin, sulfamethoxazole, sulfadiazine, ciprofloxacin hydrochloride, doxycycline hydrochloride, and trimethoprim. Firstly, we finished the determination of physiological parameters affecting solubility in chickens, including body temperature, gastrointestinal pH, and the fluid volume in the gastrointestinal tract (GI), and the drug is considered highly soluble in chicken BCS when the highest dose strength is soluble in 20.40 ml (fed) or 6.73 ml (fasted) over the pH range of 1–8 at 41°C. Drug solubility classification was based on dose number calculation. Metronidazol and amoxicillin were classed differently under fed and fasted conditions. Secondly, we discussed the effect of ABC transporters (MDCK vs. MDCK‐chAbcb1/Abcg2) and pH (5.5 vs. 7.4) on drug permeability and classification. The drug is classified as highly permeable when its permeability is equal to or greater than metoprolol tartrate. Though ABC transporters and pH significantly affected the permeability values of drugs (p <.05), the permeability classification of the drugs has not been changed except for sulfamethoxazole. This work highlights some of the significant challenges that would be encountered in order to develop a chicken BCS, this valuable information could serve as a helpful tool during chicken drugs development and to minimize the potential risks when developing formulations. [ABSTRACT FROM AUTHOR]

Drug–drug and drug–nutraceutical multicomponent solids of an antipsychotic drug olanzapine (OLN) are prepared using mechanochemistry. Drug molecules, viz., nateglinide (NAT) and pyrazinoic acid (PZO) as well as nutraceuticals, namely, 2,4,6-trihydroxybenzoic acid (246THBA), gallic acid (GA) and sinapic acid (SPA) are used as coformers in this study. After neat grinding (NG), incomplete conversion (partially amorphous) was observed, whereas liquid-assisted grinding (LAG) resulted in the formation of coamorphous OLN–NAT and crystalline salts/salt hydrates of OLN with rest of the coformers, which were characterized using a combination of techniques, including single crystal X-ray diffraction. The OLN–NAT coamorphous salt has a potential scope for development as a combination drug in order to suppress the increase in the blood sugar level, a common side-effect observed during the monotherapy of psychiatric patients using OLN. The equilibrium solubility study shows a substantial enhancement in the solubility of olanzapinium pyrazinoate compared to that of the pure base. [ABSTRACT FROM AUTHOR]

One of the major challenges for the development of drugs containing active pharmaceuticals ingredient (API) with low solubility is to add technologies to the development process in order to increase bioavailability while ensuring stability. Thus, the main objective of this work was to apply analytical methodologies in the characterization and stability of solid dispersions of atorvastatin calcium obtained by different techniques. The calorimetric curves showed different thermal profiles for the dispersions, presenting a greater interaction of the components, the SD-PEG sd. Moreover, the thermogravimetric curves showed that the PEG conferred greater stability to the dispersions. The FTIR/Pearson correlation and PXRD data revealed neither chemical interaction nor intense amorphization in the solid dispersions, respectively. Additionally, it was concluded the thermoanalytical techniques are useful, complementary, and elucidative in the characterization of the physical–chemical nature of the solid dispersions obtained by lyophilization and spray drying, providing reliable results regarding the thermal behavior and the solubility of the samples. [ABSTRACT FROM AUTHOR]

• We discuss the issue of poor drug solubility and its influence on formulation development. • Co-amorphous systems have been studied widely as a way to improve the solubility of drugs. • We review the potential of dual-drug co-amorphous systems to improve the solubility and stability of drugs. • Computational studies explain the molecular mechanisms of co-amorphous systems for dual-drug delivery. Poor solubility of drugs and therapeutic candidates poses a significant challenge in drug research and development. Biopharmaceutical class II drugs exhibit limited absorption because of their weak solubility and high permeability. Co-amorphous systems (CAMs) have been studied widely as a way to improve the solubility of drugs. This review summarizes recent advancements in dual-drug CAMs, including improvements in formulation, manufacturing, and solid-state characterization, and highlights the importance of enhancing solubility and stability. It emphasizes the potential synergistic effects of two drugs in CAMs and explores formulation strategies and challenges related to maintaining the amorphous state. Case studies demonstrate the successful application of CAMs in combination therapies that offer improved therapeutic efficacy. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel layer-by-layer approach has been introduced to build a mechanistic model for predicting drug dissolution. • The model predicted values were successfully validated with that of additively manufactured PVA polymeric tablets. • Benidipine hydrochloride loaded-PVA tablets were fabricated with four different shapes using Fused Deposition Modeling additive manufacturing method and USP Dissolution was conducted to ascertain the drug release behaviour. • Sensitivity analysis was carried out to determine the significance of parameters. Additive manufacturing has been consolidating its position in various fields over the last few decades. The development of drug delivery systems like oral tablets have been successfully accomplished using this ingenious technology. The effectiveness of an oral tablet can be analysed by its drug release behaviour and this study aims to predict this release by developing a model for a 3D printed tablet dissolution. A polymer-dissolution based mathematical model have been developed by considering a novel layer-by-layer approach that is found during additive manufacturing procedure. The shape and volume of the tablet have been found to be crucial in predicting the drug dissolution for a given time. Further, the model was verified against the drug dissolution trend obtained from a Fused Deposition Modeling (FDM)-printed polyvinyl alcohol (PVA) tablet having benidipine hydrochloride drug substance. Four different shapes have been considered to test the robustness of the model. Further, the sensitivity test have been conducted on the model and it revealed detachment rate and layer thickness as significant process parameters. [ABSTRACT FROM AUTHOR]

Cyclodextrins (CD) and derivatives are functional excipients that can improve the bioavailability of numerous drugs. Because of their drug solubility improving properties they are used in many pharmaceutical products. Furthermore, the stability of small molecular drugs can be improved by the incorporation in CDs and an unpleasant taste and smell can be masked. In addition to well-established CD derivatives including hydroxypropyl-β-CD, hydroxypropyl-γ-CD, methylated- β-CD and sulfobutylated- β-CD, there are promising new derivatives in development. In particular, CD-based polyrotaxanes exhibiting cellular uptake enhancing properties, CD-polymer conjugates providing sustained drug release, enhanced cellular uptake, and mucoadhesive properties, and thiolated CDs showing mucoadhesive, in situ gelling, as well as permeation and cellular uptake enhancing properties will likely result in innovative new drug delivery systems. Relevant clinical trials showed various new applications of CDs such as the formation of CD-based nanoparticles, stabilizing properties for protein drugs or the development of ready-to-use injection systems. Advanced products are making use of various benefical properties of CDs at the same time. Within this review we provide an overview on these recent developments and take an outlook on how this class of excipients will further shape the landscape of drug delivery. [Display omitted] [ABSTRACT FROM AUTHOR]