Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Manufacturing Processes and Analytical Technologies in Drug Product Development.

Poorly water-soluble drugs pose a significant challenge to developability due to poor oral absorption leading to poor bioavailability. Several approaches exist that improve the oral absorption of such compounds by enhancing the aqueous solubility and/or dissolution rate of the drug. These include chemical modifications such as salts, co-crystals or prodrugs and physical modifications such as complexation, nanocrystals or conversion to amorphous form. Among these formulation strategies, the conversion to amorphous form has been successfully deployed across the pharmaceutical industry, accounting for approximately 30% of the marketed products that require solubility enhancement and making it the most frequently used technology from 2000 to 2020. This article discusses the underlying scientific theory and influence of the active compound, the material properties and manufacturing processes on the selection and design of amorphous solid dispersion (ASD) products as marketed products. Recent advances in the analytical tools to characterize ASDs stability and ability to be processed into suitable, patient-centric dosage forms are also described. The unmet need and regulatory path for the development of novel ASD polymers is finally discussed, including a description of the experimental data that can be used to establish if a new polymer offers sufficient differentiation from the established polymers to warrant advancement.

Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic.

Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.

Antioxidant activity of Syzygium cumini leaf gall extracts.

INTRODUCTION: Free radicals are implicated in several metabolic diseases and the medicinal properties of plants have been explored for their potent antioxidant activities to counteract metabolic disorders. This research highlights the chemical composition and antioxidant potential of leaf gall extracts (aqueous and methanol) of Syzygium cumini (S. cumini), which have been extensively used in traditional medications to treat various metabolic diseases. METHODS: The antioxidant activities of leaf gall extracts were examined using diphenylpicrylhydrazyl (DPPH), nitric oxide scavenging, hydroxyl scavenging and ferric reducing power (FRAP) methods. RESULTS: In all the methods, the methanolic extract showed higher antioxidant potential than the standard ascorbic acid. The presence of phenolics, flavonoids, phytosterols, terpenoids, and reducing sugars was identified in both the extracts. When compared, the methanol extract had the highest total phenolic and flavonoid contents at 474±2.2 mg of GAE/g d.w and 668±1.4 mg of QUE/g d.w, respectively. The significant high antioxidant activity can be positively correlated to the high content of total polyphenols/flavonoids of the methanol extract. CONCLUSION: The present study confirms the folklore use of S. cumini leaves gall extracts as a natural antioxidant and justifies its ethnobotanical use. Further, the result of antioxidant properties encourages the use of S. cumini leaf gall extracts for medicinal health, functional food and nutraceuticals applications.

The impact of roller compaction and tablet compression on physicomechanical properties of pharmaceutical excipients.

Material properties play a significant role in pharmaceutical processing. The impact of roller compaction (RC) and tablet compression on solid fraction (SF), tensile strength (TS) and flexural modulus (FM) of Avicel DG [co-processed excipient with 75% microcrystalline cellulose (MCC) and 25% anhydrous dibasic calcium phosphate (DCPA)], lactose and 1:1 Mixture of the two was studied. Materials were roller compacted at different force and roller type and compressed into tablets over a range of compression pressures (CP). SF, TS and FM were determined for ribbons and tablets. Roller force was a significant variable affecting SF while roller type was not. Both SF and TS of tablets increased with CP with Avicel DG exhibiting greater TS than that of 1:1 Mixture while tablets of lactose had the lowest TS. The TS of tablets decreased exponentially with tablet porosity. Ribbon of Avicel DG had higher TS and lower SF than lactose and greater reworkability. This is attributed to plastic deformation of MCC resulting in high degree of bonding and fragmentation of DCPA that fills the void spaces during tablet compression. The lack of significant increase in SF and low tablet TS for lactose upon compression is likely due to its brittle fragmentation and some elastic recovery as shown by the high FM.

A novel approach to determine solid fraction using a laser-based direct volume measurement device.

Material properties play a significant role in pharmaceutical processing. In the present study, a novel approach is used to determine solid fraction (SF) based on a direct measurement (DM) of the apparent volume of a sample. The sample was scanned with low intensity laser beams that integrate the sample thickness across the surface (area) and quantitate the apparent volume. The SF by DM method was compared against that obtained by volume displacement (VD) and manual measurement methods. SF was determined by all three methods for formulations of Avicel DG, lactose and a 1:1 mixture of the two. The results from DM method and variability were comparable to that obtained by VD method. The manual method provided lower and more variable results. The DM method was able to differentiate between SF of different ribbon and tablet formulations and at varying force levels. Tracking SF of compacts during tablet development can help in setting acceptable specifications and to understand material deformation behavior during compression. Further, the results of the study indicate that the DM method using laser scan technique was suitable for routine testing of SF of roller compacted ribbons and compressed tablets.

Stability assessment of hypromellose acetate succinate (HPMCAS) NF for application in hot melt extrusion (HME).

HPMCAS is a widely used polymer in the pharmaceutical industry as an excipient. In this work, the physicochemical stability of HPMCAS was investigated for hot melt extrusion (HME) application. The reduction in zero rate viscosity (η0) of the polymer with the increase in temperature was determined using rheological evaluation prior to HME processing. The energy of activation for AS-MF determined by fitting Arrhenius model to the temperature dependent reduction in η0 was found to be slightly lower than that for the other grades of HPMCAS. Glassy yellowish HMEs were obtained using Haake Mini-Lab MicroCompounder operated at 160, 180, and 200°C and 100, 200, and 300 rpm for all the grades at each temperature. Various physicochemical properties of HPMCAS such as glass transition temperature, semi-crystalline nature, solid state functional group properties, moisture content, and solution viscosity were not significantly affected by the HME processing. The most significant change was the release of acetic and succinic acid with the increase in HME temperature and speed. The free acid content release due to HME was directly proportional to the speed at lower operating temperatures. AS-LF was found to be the most stable with the lowest increase in total free acid content even at higher HME temperature and speed. Although the dissolution time was not affected due to HME for AS-LF and AS-MF grades, it was notably increased for AS-HF, perhaps due to significant reduction of succinoyl content. In conclusion, the HME processing conditions for solid dispersions of HPMCAS should be based on the acceptance levels of free acid for the drug and the drug product.

The impact of hot melt extrusion and spray drying on mechanical properties and tableting indices of materials used in pharmaceutical development.

The impact of melt extrusion (HME) and spray drying (SD) on mechanical properties of hypromellose acetate succinate (HPMCAS), copovidone, and their formulated blends was studied and compared with that of reference excipients. Tensile strength (TS), compression pressure (CP), elastic modulus (E), and dynamic hardness (Hd ) were determined along with Hiestand indices using compacts prepared at a solid fraction of ∼0.85. HPMCAS and copovidone exhibited lower Hd , lower CP, and lower E than the reference excipients and moderate TS. HPMCAS was found to be highly brittle based on brittle fracture index values. The CP was 24% and 61% higher for HPMCAS after SD and HME, respectively, than for unprocessed material along with a higher Hd . Furthermore, the TS of HPMCAS and copovidone decreased upon HME. Upon blending melt-extruded HPMCAS with plastic materials such as microcrystalline cellulose, the TS increased. These results suggest that SD and HME could impact reworkability by reducing deformation of materials and in case of HME, likely by increasing density due to heating and shear stress in a screw extruder. A somewhat similar effect was observed for the dynamic binding index (BId ) of the excipients and formulated blends. Such data can be used to quantitate the impact of processing on mechanical properties of materials during tablet formulation development.

Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process.

The present work deals with improving the solubility of vemurafenib, a practically insoluble drug, by converting it into an amorphous-solid dispersion using a solvent-controlled precipitation process. The dispersion containing vemurafenib and hypromellose acetate succinate (HPMCAS), an enteric polymer, is termed microprecipitated bulk powder (MBP), in which the drug is uniformly dispersed within the polymeric substrate. HPMCAS was found to be the most suitable polymer for vemurafenib MBP, among a series of enteric polymers based on superior physical stability and drug-release characteristics of the MBP. The MBP provided a greater rate and extent of dissolution than crystalline drug, reaching an apparent drug concentration of 28-35 µg/mL, almost 30-fold higher than solubility of crystalline drug at 1 µg/mL. The supersaturation was also maintained for more than 4 h. Upon exposure to high temperature and humidity, the MBP was destabilized, resulting in crystallization and lower dissolution rate. The control of moisture and temperature is essential to maintain the stability of the MBP. In a relative human bioavailability study, vemurafenib MBP provided a four- to fivefold increase in exposure compared with crystalline drug. Improving solubility with an amorphous-solid dispersion is a viable strategy for the development of practically insoluble compounds.

Development of novel microprecipitated bulk powder (MBP) technology for manufacturing stable amorphous formulations of poorly soluble drugs.

A novel method was developed to manufacture amorphous formulations of poorly soluble compounds that cannot be processed with existing methods such as spray drying and melt extrusion. The manufacturing process and the characterization of the resulting amorphous dispersion are presented via examples of two research compounds. The novel process is utilized N,N-dimethylacetamide (DMA) to dissolve the drug and the selected ionic polymer. This solution is then co-precipitated into aqueous medium. The solvent is extracted out by washing and the co-precipitated material is isolated by filtration followed by drying. The dried material is referred to as microprecipitated bulk powder (MBP). The amorphous form prepared using this method not only provides excellent in vitro and in vivo performance but also showed excellent stability. The stabilization of amorphous dispersion is attributed to the high T(g), ionic nature of the polymer that help to stabilize the amorphous form by possible ionic interactions, and/or due to the insolubility of polymer in water. In addition to being an alternate technology for amorphous formulation of difficult compounds, MBP technology provides advantages with respect to stability, density and downstream processing.

Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma.

B-RAF is the most frequently mutated protein kinase in human cancers. The finding that oncogenic mutations in BRAF are common in melanoma, followed by the demonstration that these tumours are dependent on the RAF/MEK/ERK pathway, offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts. Toxicology studies confirmed a wide safety margin consistent with the high degree of selectivity, enabling Phase 1 clinical trials using a crystalline formulation of PLX4032 (ref. 5). In a subset of melanoma patients, pathway inhibition was monitored in paired biopsy specimens collected before treatment initiation and following two weeks of treatment. This analysis revealed substantial inhibition of ERK phosphorylation, yet clinical evaluation did not show tumour regressions. At higher drug exposures afforded by a new amorphous drug formulation, greater than 80% inhibition of ERK phosphorylation in the tumours of patients correlated with clinical response. Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily. These data demonstrate that BRAF-mutant melanomas are highly dependent on B-RAF kinase activity.

RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models.

The BRAF(V600E) mutation is common in several human cancers, especially melanoma. RG7204 (PLX4032) is a small-molecule inhibitor of BRAF(V600E) kinase activity that is in phase II and phase III clinical testing. Here, we report a preclinical characterization of the antitumor activity of RG7204 using established in vitro and in vivo models of malignant melanoma. RG7204 potently inhibited proliferation and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and ERK phosphorylation in a panel of tumor cell lines, including melanoma cell lines expressing BRAF(V600E) or other mutant BRAF proteins altered at codon 600. In contrast, RG7204 lacked activity in cell lines that express wild-type BRAF or non-V600 mutations. In several tumor xenograft models of BRAF(V600E)-expressing melanoma, we found that RG7204 treatment caused partial or complete tumor regressions and improved animal survival, in a dose-dependent manner. There was no toxicity observed in any dose group in any of the in vivo models tested. Our findings offer evidence of the potent antitumor activity of RG7204 against melanomas harboring the mutant BRAF(V600E) gene.

Characterization of physico-mechanical properties of indomethacin and polymers to assess their suitability for hot-melt extrusion processs as a means to manufacture solid dispersion/solution.

The objective of the study was to characterize the physical and viscoelastic properties of binary mixtures of drug and selected polymers to assess their suitability for use in the hot-melt extrusion (HME) process as a means to improve solubility by manufacturing either solid dispersion or solid solution. Indomethacin (INM) was selected as a model drug. Based on comparable solubility parameters, the selected polymers were Eudragit EPO (EPO), polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA), polyvinylpyrrolidone K30 (PVPK30), and poloxamer 188 (P188). The various drug and polymer systems were characterized for thermal and rheological properties as a function of drug concentration to provide an insight into miscibility and processibility of these systems. From the thermal analysis studies, a single T(g) was observed for the binary mixtures of INM/EPO, INM/PVP-VA, and INM/PVPK30, indicating miscibility of drug and polymer in the given ratios. In the case of mixtures of INM/P188, two melting endotherms were observed with decreasing drug melting point as a function of polymer concentration indicating partial miscibility of drug in polymer. As part of the rheological evaluation, zero rate viscosity (eta(o)) and activation energy (E(a)) was determined for the various systems using torque rheometer at varying shear rates and temperatures. The eta(o) for binary mixtures of drug and EPO, PVP-VA and PVPK30 were found to be significantly lower as compared to pure polymer, indicating disruption of the polymer structure due to miscibility of the drug. On the other hand, INM/P188 mixtures showed a higher eta(o) compared to pure polymer indicating partial miscibility of drug and polymer. With respect to E(a), the mixtures of INM/EPO showed an increase in E(a) with increasing drug concentration, suggesting antiplasticization effect of the drug. These findings corroborate the thermal analysis results showing increase T(g) for the various binary mixtures. The mixtures of INM/PVP-VA showed a decrease in the E(a) with the increasing drug concentration suggesting a plasticization effect of the drug. The understanding of thermal and rheological properties of the various drug/polymer mixtures help established the processing conditions for hotmelt extrusion (such as extrusion temperatures and motor load) as well as provided insight into the properties of the final extrudates. Using the actual hot-melt processing, a model was developed correlating the zero rate viscosity to the motor load determined by rheological evaluation.