Effect of Buffer pH and Concentration on the Dissolution Rates of Sodium Indomethacin-Copovidone and Indomethacin-Copovidone Amorphous Solid Dispersions.

The incorporation of counterions into amorphous solid dispersions (ASDs) has been proven to be effective for improving the dissolution rates of ionizable drugs in ASDs. In this work, the effect of dissolution buffer pH and concentration on the dissolution rate of indomethacin-copovidone 40:60 (IMC-PVPVA, w/w) ASD with or without incorporated sodium hydroxide (NaOH) was studied by surface area-normalized dissolution to provide further mechanistic understanding of this phenomenon. Buffer pH from 4.7 to 7.2 and concentration from 20 to 100 mM at pH 5.5 were investigated. As the buffer pH decreased, the IMC dissolution rate from both ASDs decreased. Compared to IMC-PVPVA ASD, the dissolution rate decrease from IMCNa-PVPVA ASD was more resistant to the decrease of buffer pH. In contrast, while buffer concentration had a negligible impact on the IMC dissolution rate from IMC-PVPVA ASD, the increase of buffer concentration significantly reduced the IMC dissolution rate from IMCNa-PVPVA ASD. Surrogate evaluation of microenvironment pH modification by the dissolution of IMCNa-PVPVA ASD demonstrated the successful elevation of buffer microenvironment pH and the suppression of such pH elevation by the increase of buffer concentration. These results are consistent with the hypothesis that the dissolution rate enhancement by the incorporation of counterions originates from the enhanced drug solubility by ionization and the modification of diffusion layer pH in favor of drug dissolution. At the studied drug loading (∼40%), relatively congruent release between IMC and PVPVA was observed when IMC was ionized in ASD or in solution, highlighting the importance of studying the ionization effect on the congruent release of ASDs, especially when drug ionization is expected in vivo. Overall, this work further supports the application of incorporating counterions into ASDs for improving the dissolution rates of ionizable drugs when enabling formulation development is needed.

Molecular Interactions between APIs and Enteric Polymeric Excipients in Solid Dispersion: Insights from Molecular Simulations and Experiments.

Solid dispersion of poorly soluble APIs is known to be a promising strategy to improve dissolution and oral bioavailability. To facilitate the development and commercialization of a successful solid dispersion formulation, understanding of intermolecular interactions between APIs and polymeric carriers is essential. In this work, first, we assessed the molecular interactions between various delayed-release APIs and polymeric excipients using molecular dynamics (MD) simulations, and then we formulated API solid dispersions using a hot melt extrusion (HME) technique. To assess the potential API-polymer pairs, three quantities were evaluated: (a) interaction energy between API and polymer [electrostatic (Ecoul), Lenard-Jones (ELJ), and total (Etotal)], (b) energy ratio (API-polymer/API-API), and (c) hydrogen bonding between API and polymer. The Etotal quantities corresponding to the best pairs: NPX-Eudragit L100, NaDLO-HPMC(P), DMF-HPMC(AS) and OPZ-HPMC(AS) were -143.38, -348.04, -110.42, and -269.43 kJ/mol, respectively. Using a HME experimental technique, few API-polymer pairs were successfully extruded. These extruded solid forms did not release APIs in a simulated gastric fluid (SGF) pH 1.2 environment but released them in a simulated intestinal fluid (SIF) pH 6.8 environment. The study demonstrates the compatibility between APIs and excipients, and finally suggests a potential polymeric excipient for each delayed-release API, which could facilitate the development of the solid dispersion of poorly soluble APIs for dissolution and bioavailability enhancement.

Formulation and In Vitro Characterization of a Vacuum-Dried Drug-Polymer Thin Film for Intranasal Application.

Intranasal drug applications show significant therapeutic potential for diverse pharmaceutical modalities. Because the formulation applied to the nasal cavity is discharged to the pharyngeal side by mucociliary clearance, the formulation should be dissolved effectively in a limited amount of mucus within its retention time in the nasal cavity. In this study, to develop novel formulations with improved dissolution behavior and compatibility with the intranasal environment, a thin-film formulation including drug and polymer was prepared using a vacuum-drying method. The poorly water-soluble drugs ketoprofen, flurbiprofen, ibuprofen, and loxoprofen were dissolved in a solvent comprising water and methanol, and evaporated to obtain a thin film. Physical analyses using differential scanning calorimetry (DSC), powder X-ray diffraction analysis (PXRD), and scanning electron microscopy SEM revealed that the formulations were amorphized in the film. The dissolution behavior of the drugs was investigated using an in vitro evaluation system that mimicked the intranasal physiological environment. The amorphization of drugs formulated with polymers into thin films using the vacuum-drying method improved the dissolution rate in artificial nasal fluid. Therefore, the thin film developed in this study can be safely and effectively used for intranasal drug application.

Computational approach to elucidate the formation and stabilization mechanism of amorphous formulation using molecular dynamics simulation and fragment molecular orbital calculation.

α-Glycosyl rutin (Rutin-G) consists of a flavonol skeleton and sugar groups and is a promising additive for amorphous formulations. In our previous study, experimental approaches suggested an interaction between the model drug carbamazepine (CBZ) and flavonol skeleton of Rutin-G that stabilizes amorphous formulations. In the present study, the formation and stabilization mechanisms of CBZ/Rutin-G amorphous formulation were investigated using a computational approach. The CBZ/Rutin-G amorphous formulation was obtained via molecular dynamics (MD) simulation, which mimicked the melt-quenching method. Root mean square deviation analysis revealed that the translational motion of CBZ during the cooling process was suppressed by adding Rutin-G. Monitoring the atomic distance during the cooling process revealed that hydrogen bonds via carboxamide oxygen of CBZ with hydroxyl hydrogen of Rutin-G were preferentially formed with flavonol skeletons than sugar groups. The simulated amorphous formulation was then calculated using fragment molecular orbital (FMO) method. The quantitative evaluation of multiple interactions revealed that the hydrogen bond energy was higher in CBZ-sugar groups than in CBZ-flavonol skeleton, while the π-type of interaction energy was higher in CBZ-flavonol skeleton than in CBZ-sugar groups. The computational approach combining MD simulation and FMO calculation provides information on various interactions that are difficult to detect using experimental approaches, which helps understand the formation and stabilization mechanism of amorphous formulations.

Recent Technologies for Amorphization of Poorly Water-Soluble Drugs.

Amorphization technology has been the subject of continuous attention in the pharmaceutical industry, as a means to enhance the solubility of poorly water-soluble drugs. Being in a high energy state, amorphous formulations generally display significantly increased apparent solubility as compared to their crystalline counterparts, which may allow them to generate a supersaturated state in the gastrointestinal tract and in turn, improve the bioavailability. Conventionally, hydrophilic polymers have been used as carriers, in which the amorphous drugs were dispersed and stabilized to form polymeric amorphous solid dispersions. However, the technique had its limitations, some of which include the need for a large number of carriers, the tendency to recrystallize during storage, and the possibility of thermal decomposition of the drug during preparation. Therefore, emerging amorphization technologies have focused on the investigation of novel amorphous-stabilizing carriers and preparation methods that can improve the drug loading and the degree of amorphization. This review highlights the recent pharmaceutical approaches utilizing drug amorphization, such as co-amorphous systems, mesoporous particle-based techniques, and in situ amorphization. Recent updates on these technologies in the last five years are discussed with a focus on their characteristics and commercial potential.

Stabilization mechanism of amorphous carbamazepine by transglycosylated rutin, a non-polymeric amorphous additive with a high glass transition temperature.

α-Glycosyl rutin (Rutin-G), composed of a flavonol skeleton and sugar groups, is a promising non-polymeric additive for stabilizing amorphous drug formulations. In this study, the mechanism of the stabilization of the amorphous state of carbamazepine (CBZ) by Rutin-G was investigated. In comparison with hypromellose (HPMC), which is commonly used as a crystallization inhibitor for amorphous drugs, Rutin-G significantly stabilized amorphous CBZ. Moreover, the dissolution rate and the resultant supersaturation level of CBZ were significantly improved in the CBZ/Rutin-G spray-dried samples (SPDs) owing to the rapid dissolution property of Rutin-G. Differential scanning calorimetry measurement demonstrated a high glass transition temperature (Tg) of 186.4°C corresponding to Rutin-G. The CBZ/Rutin-G SPDs with CBZ weight ratios up to 80% showed single glass transitions, indicating the homogeneity of CBZ and Rutin-G. A solid-state NMR experiment using 13C- and 15N-labeled CBZ demonstrated the interaction between the flavonol skeleton of Rutin-G and the amide group of CBZ. A 1H-13C two-dimensional heteronuclear correlation NMR experiment and quantum mechanical calculations confirmed the presence of a possible hydrogen bond between the amino proton in CBZ and the carbonyl oxygen in the flavonol skeleton of Rutin-G. This specific hydrogen bond could contribute to the strong interaction between CBZ and Rutin-G, resulting in the high stability of amorphous CBZ in the CBZ/Rutin-G SPD. Hence, Rutin-G, a non-polymeric amorphous additive with high Tg, high miscibility with drugs, and rapid and pH-independent dissolution properties could be useful in the preparation of amorphous formulations.

Impact of polymer type, ASD loading and polymer-drug ratio on ASD tablet disintegration and drug release.

Amorphous solid dispersion (ASD) has become an attractive strategy to enhance solubility and bioavailability of poorly water-soluble drugs. To facilitate oral administration, ASDs are commonly incorporated into tablets. Disintegration and drug release from ASD tablets are thus critical for achieving the inherent solubility advantage of amorphous drugs. In this work, the impact of polymer type, ASD loading in tablet and polymer-drug ratio in ASD on disintegration and drug release of ASD tablets was systematically studied. Two hydrophilic polymers PVPVA and HPMC and one relatively hydrophobic polymer HPMCAS were evaluated. Dissolution testing was performed, and disintegration time was recorded during dissolution testing. As ASD loading increased, tablet disintegration time increased for all three polymer-based ASD tablets, and this effect was more pronounced for hydrophilic polymer-based ASD tablets. As polymer-drug ratio increased, tablet disintegration time increased for hydrophilic polymer-based ASD tablets, however, it remained short and largely unchanged for HPMCAS-based ASD tablets. Consequently, at high ASD loadings or high polymer-drug ratios, HPMCAS-based ASD tablets showed faster drug release than PVPVA- or HPMC-based ASD tablets. These results were attributed to the differences between polymer hydrophilicities and viscosities of polymer aqueous solutions. This work is valuable for understanding the disintegration and drug release of ASD tablets and provides insight to ASD composition selection from downstream tablet formulation perspective.

Measurement of the amorphous fraction of olanzapine incorporated in a co-amorphous formulation.

Amorphous and co-amorphous formulations have been used to enhance the solubility and bioavailability of poorly water-soluble drugs. However, during handling and/or storage amorphous solids present inherent instability and overtime recrystallize back into their crystalline counterpart. The development of tools capable of quantifying and monitoring the recrystallization of amorphous materials is required to ensure the delivery of solid dosage forms with improved performance. This work describes the development and validation of a computational model for simple measurement of amorphous and co-amorphous olanzapine (OLZ) fractions in tablets. Amorphous OLZ produced by quench cooling and co-amorphous OLZ by solvent evaporation using saccharin (SAC) as a co-former were characterized by calorimetry (DSC), diffractometry (XRPD) and spectroscopy (FTIR and NIR). Spectral differences were used to predict the fraction of amorphous OLZ in samples containing different fractions of powdered amorphous and co-amorphous OLZ:SAC. The models were shown to be linear, accurate and reproducible. Blends of (co)amorphous OLZ and excipients were directly compacted at different pressures and dwell times to impose physical stress on the systems. Data collected from the analysis of the tablets was used in the model to monitor the stability of amorphous and co-amorphous OLZ demonstrating the applicability and validity of the model.

Effect of primary drying temperature on process efficiency and product performance of lyophilized Ertapenam sodium.

The present work aimed to investigate the impact of primary drying temperature on lyophilization process efficiency and product performance of lyophilized Ertapenam sodium (EPM). Phase behavior of EPM formulation (200 mg/mL) using differential scanning calorimetry (DSC) and freeze drying microscopy (FDM) showed Tg' at -28.3 °C (onset) and Tc at -25.0 °C (onset), respectively. The formulation was freeze dried at different product temperature (Tp) during primary drying, using (a) conservative cycle (CC) where the maximum Tp (-31.9 °C) Tg', and (c) AC02 where the maximum Tp (-21.0 °C) >Tc. The drying kinetics revealed that the sublimation rate was increased from 0.128 g/h/vial in CC to 0.159 and 0.182 g/h/vial in AC01 and AC02, respectively. This ultimately reduced the primary drying time of 208 min in CC to 145 min in AC01 and to 103 minutes in AC02. Morphological evaluation of cake using scanning electron microscopy (SEM) and texture analysis revealed that AC01 lead to induction of microcollapse, whereas AC02 resulted in collapsed cake. Furthermore, the microcollapsed formulations showed similar physicochemical stability to CC formulation, whereas collapsed cake showed significant degradation of EPM and increased degradation on stress stability. The study highlights that primary drying with microcollapse can be utilized to improve the process efficiency without compromising product quality of amorphous EPM.

Assessing the Impact of Endogenously Derived Crystalline Drug on the in Vivo Performance of Amorphous Formulations.

Crystallization of drug from an amorphous formulation is expected to negatively impact its bioperformance following oral delivery. In evaluating this in vivo, neat crystalline drug is typically mixed with the amorphous formulation. However, this approach may not adequately mimic the effect of drug crystals that form within the amorphous matrix, because crystal properties are highly dependent on the crystallization environment. The aim of this study was to evaluate the in vivo impact of crystals formed in a generic tacrolimus amorphous formulation, relative to noncrystallized formulations and a reference suspension containing neat crystalline drug. Crystallization of tacrolimus was induced in the generic product by exposing it to moderate temperatures and high relative humidity. Controlled levels of crystallinity in the formulations were achieved by mixing maximally crystallized and fresh formulations at the desired ratios. These formulations were then characterized in vitro and used for oral dosing to beagle dogs. Analysis of blood concentrations versus time revealed that formulations containing 50 and 100% crystalline tacrolimus resulted in lower area under the curve (AUC) and maximum concentration (Cmax) values as compared to the fresh amorphous formulation. However, the AUC and the Cmax values for these formulations were significantly higher than those observed after dosing the pure crystalline tacrolimus suspension. The innovator formulation, Prograf, showed comparable pharmacokinetics before and after exposure to accelerated stability conditions, confirming the robustness of the innovator product to drug crystallization. This study provides insight into the impact of endogenously crystallized material on the oral absorption of a poorly water-soluble compound and highlights the importance of using representative crystalline material when undertaking risk assessment of amorphous formulations.

Surface Dissolution UV Imaging for Investigation of Dissolution of Poorly Soluble Drugs and Their Amorphous Formulation.

The aim of this study is to investigate the dissolution properties of poorly soluble drugs from their pure form and their amorphous formulation under physiological relevant conditions for oral administration based on surface dissolution ultraviolet (UV) imaging. Dissolution of two poorly soluble drugs (cefuroxime axetil and itraconazole) and their amorphous formulations (Zinnat® and Sporanox®) was studied with the Sirius Surface Dissolution Imager (SDI). Media simulating the fasted state conditions (compendial and biorelevant) with sequential media/flow rate change were used. The dissolution mechanism of cefuroxime axetil in simulated gastric fluid (SGF), fasted state simulated gastric fluid (FaSSGF) and simulated intestinal fluid (SIF) is predominantly swelling as opposed to the convective flow in fasted state simulated intestinal fluid (FaSSIF-V1), attributed to the effect of mixed micelles. For the itraconazole compact in biorelevant media, a clear upward diffusion of the dissolved itraconazole into the bulk buffer solution is observed. Dissolution of itraconazole from the Sporanox® compact is affected by the polyethylene glycol (PEG) gelling layer and hydroxypropyl methylcellulose (HPMC) matrix, and a steady diffusional dissolution pattern is revealed. A visual representation and a quantitative assessment of dissolution properties of poorly soluble compounds and their amorphous formulation can be obtained with the use of surface dissolution imaging under in vivo relevant conditions.

Investigations of the mechanism behind the rapid absorption of nano-amorphous abiraterone acetate.

Abiraterone acetate is indicated for patients with metastatic castration resistant prostate cancer. The marketed drug product (Zytiga®) exhibits very low bioavailability in the fasted state and a substantial positive food effect. We recently developed a nano-amorphous formulation of this drug which exhibited higher apparent solubility and dissolution rate, and significantly improved absorption and bioavailability in the fasted state in beagle dogs and in a phase I clinical study. One surprising finding, however, was the very rapid absorption observed both in dogs and in humans with median tmax values in the 0.5-0.75 h range. This could not be explained by the improved dissolution characteristics alone. A recent study showed that following the administration of Zytiga® abiraterone acetate is converted to abiraterone in the intestinal lumen yielding supersaturated abiraterone concentrations, which is believed to be the driving force of the absorption process. In our work we found that the enzymatic hydrolysis of abiraterone acetate profoundly changes the pharmacokinetics of the nano-amorphous formulation in the fasted state and it is the most probable reason for the unexpectedly high absorption rate. Our primary candidate for the isoenzyme involved is pancreatic cholesterol esterase. Furthermore, we identified orlistat as a potent inhibitor of cholesterol esterase and found it to be an ideal compound for the study of the enzymatic process in vivo. The observed inhibition could result in a clinically significant modification of abiraterone pharmacokinetics, which might make a drug interaction warning necessary for abiraterone acetate containing drugs. The mathematical and experimental tools presented in this work might be suitable for the study of the contribution of other intestinal enzymatic processes to the absorption process of other prodrugs as well.

PBPK Absorption Modeling of Food Effect and Bioequivalence in Fed State for Two Formulations with Crystalline and Amorphous Forms of BCS 2 Class Drug in Generic Drug Development.

Prediction of the effect of food on drug's pharmacokinetics using modeling and simulation could cause difficulties due to complex in vivo processes. A generic formulation with amorphous form of BCS 2 class drug substance was developed and compared in vitro and in vivo to the reference drug product with drug substance in crystalline form. In order to approve generic formulation, some regulatory agencies are requesting to perform bioequivalence (BE) studies also in fed state. Food can have various effects on drug dissolution and absorption, depending also on drug's properties. A physiologically based pharmacokinetic (PBPK) absorption model was built in GastroPlus™ to predict the food effect on generic and reference formulation and to predict the fed BE study outcome. During model development, we were searching for model inputs that impact and describe in vivo behavior of amorphous and crystalline forms of active pharmaceutical ingredient (API) in fast and fed conditions. The developed model was able to predict the food effect with up to 10% prediction error (PE). Performed virtual BE trials confirmed the BE of drug products in fed state. Our model was able to capture the difference between the two drug products containing different forms of API (amorphous and crystalline) and predict the food effect on both formulations.

Towards a better understanding of solid dispersions in aqueous environment by a fluorescence quenching approach.

Solid dispersions (SDs) represent an important formulation technique to achieve supersaturation in gastro-intestinal fluids and to enhance absorption of poorly water-soluble drugs. Extensive research was leading to a rather good understanding of SDs in the dry state, whereas the complex interactions in aqueous medium are still challenging to analyze. This paper introduces a fluorescence quenching approach together with size-exclusion chromatography to study drug and polymer interactions that emerge from SDs release testing in aqueous colloidal phase. Celecoxib was used as a model drug as it is poorly water-soluble and also exhibits native fluorescence so that quenching experiments were enabled. Different pharmaceutical polymers were evaluated by the (modified) Stern-Volmer model, which was complemented by further bulk analytics. Drug accessibility by the quencher and its affinity to celecoxib were studied in physical mixtures as well as with in SDs. The obtained differences enabled important molecular insights into the different formulations. Knowledge of relevant drug-polymer interactions and the amount of drug embedded into polymer aggregates in the aqueous phase is of high relevance for understanding of SD performance. The novel fluorescence quenching approach is highly promising for future research and it can provide guidance in early formulation development of native fluorescent compounds.

Novel Iron-Whey Protein Microspheres Protect Gut Epithelial Cells from Iron-Related Oxidative Stress and Damage and Improve Iron Absorption in Fasting Adults.

BACKGROUND: Iron food fortification and oral iron formulations are frequently limited by poor absorption, resulting in the widespread use of high-dose oral iron, which is poorly tolerated. METHODS: We evaluated novel iron-denatured whey protein (Iron-WP) microspheres on reactive oxygen species (ROS) and viability in gut epithelial (HT29) cells. We compared iron absorption from Iron-WP versus equimolar-dose (25 mg elemental iron) ferrous sulphate (FeSO4) in a prospective, randomised, cross-over study in fasting volunteers (n = 21 per group) dependent on relative iron depletion (a ferritin level ≤/>30 ng/mL). RESULTS: Iron-WP caused less ROS generation and better HT29 cell viability than equimolar FeSO4. Iron-WP also showed better absorption with a maximal 149 ± 39% increase in serum iron compared to 65 ± 14% for FeSO4 (p = 0.01). The response to both treatments was dependent on relative iron depletion, and multi-variable analysis showed that better absorption with Iron-WP was independent of baseline serum iron, ferritin, transferrin saturation, and haemoglobin in the overall group and in the sub-cohort with relative iron depletion at baseline (p < 0.01). CONCLUSIONS: Novel Iron-WP microspheres may protect gut epithelial cells and improve the absorption of iron versus FeSO4. Further evaluation of this approach to food fortification and supplementation with iron is warranted.

Enhanced oral delivery of celecoxib via the development of a supersaturable amorphous formulation utilising mesoporous silica and co-loaded HPMCAS.

Stabilization of amorphous formulations via mesoporous silica has gained considerable attention for oral delivery of poorly soluble drugs. The release of the drug from the silica is expected to generate supersaturation which is often associated with subsequent precipitation. The aim of the study was hence to develop a novel supersaturable amorphous formulation through the co-loading of a BCS class II drug Celecoxib (CXB) with a precipitation inhibitor hydroxypropyl methylcellulose acetate succinate (HPMCAS) onto the silica. The addition of HPMCAS did not hamper the adsorption but on the contrary promoted the complete solid state conversion of the drug as proved by DSC analysis. In an in vitro pH shift assay, the CXB-HPMCAS co-loaded silica achieved a 5-fold solubility increase over the crystalline CXB and over the CXB-loaded silica blended with HPMCAS which did not show any enhancement. The drug co-loaded silica was then suspended in an aqueous vehicle facilitating the dosing to animals. The CXB-HPMCAS co-loaded silica suspension achieved 15-fold solubility increase in vitro over the crystalline counterpart which translated in 1.35-fold Cmax increase in vivo after oral dosing in rats. This approach represents a novel formulation strategy to maximize in vivo exposure of poorly soluble drugs critical for discovery studies.

Haste Makes Waste: The Interplay Between Dissolution and Precipitation of Supersaturating Formulations.

Contrary to the early philosophy of supersaturating formulation design for oral solid dosage forms, current evidence shows that an exceedingly high rate of supersaturation generation could result in a suboptimal in vitro dissolution profile and subsequently could reduce the in vivo oral bioavailability of amorphous solid dispersions. In this commentary, we outline recent research efforts on the specific effects of the rate and extent of supersaturation generation on the overall kinetic solubility profiles of supersaturating formulations. Additional insights into an appropriate definition of sink versus nonsink dissolution conditions and the solubility advantage of amorphous pharmaceuticals are also highlighted. The interplay between dissolution and precipitation kinetics should be carefully considered in designing a suitable supersaturating formulation to best improve the dissolution behavior and oral bioavailability of poorly water-soluble drugs.