Production Of Solid Dispersions Research Articles

Electromagnetic drop-on-demand (DoD) technology as an innovative platform for amorphous solid dispersion production

Production of amorphous solid dispersions (ASDs) is an effective strategy to promote the solubility and bioavailability of poorly water soluble medicinal substances. In general, ASD is manufactured using a variety of classic and modern techniques, most of which rely on either melting or solvent evaporation. This proof-of-concept study is the first ever to introduce electromagnetic drop-on-demand (DoD) technique as an alternative solvent evaporation-based method for producing ASDs. Herein 3D printing of ASDs for three drug-polymer combinations (efavirenz-Eudragit L100-55, lumefantrine-hydroxypropyl methylcellulose acetate succinate, and favipiravir-polyacrylic acid) was investigated to ascertain the reliability of this technique. Polarized light microscopy, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and Fourier Transform Infrared (FTIR) spectroscopy results supported the formation of ASDs for the three drugs by means of DoD 3D printing, which significantly increases the equilibrium solubility of efavirenz from 0.03 ± 0.04 µg/ml to 21.18 ± 4.20 µg/ml, and the equilibrium solubility of lumefantrine from 1.26 ± 1.60 µg/ml to 20.21 ± 6.91 µg/ml. Overall, the reported findings show how this new electromagnetic DoD technology can have a potential to become a cutting-edge 3D printing solvent-evaporation technique for on-demand and continuous manufacturing of ASDs for a variety of drugs.

Formulation of mouth-dissolving tablets containing a spray-dried solid dispersion of poorly water-soluble fenoprofen calcium dihydrate and its characterization

The aim and objective of this investigation focus on the formulation of mouth-dissolving tablets of Fenoprofen calcium dihydrate spray dried solid dispersions. Materials and methods. Spray drying is a well-recognized manufacturing technique that can be used to create amorphous solid dispersions, which are an effective delivery method for poorly water-soluble pharmaceuticals such as Fenoprofen calcium dihydrate (FCD). In addition to skimmed milk powder (SMP) and FCD, the carrier β-cyclodextrin was used to produce solid dispersions. Results and discussion. The production of solid dispersions yielded reproducible results. Solid dispersion with β-cyclodextrin and skimmed milk powder is one way to increase disintegration time by increasing the water solubility of inadequately water-soluble FCD. In-vitro dissolution experiments of FCD mouth-dissolving tablets revealed significant differences. Stability studies should evaluate drug product characteristics that are susceptible to change during storage and are anticipated to impact quality, safety, and efficacy to demonstrate that the optimal formulations remain stable over the course of the study. The results of stability experiments were statistically significant at p<0.05 using one-way ANOVA followed by Dunnet's test. During in-vivo anti-inflammatory experiments, the formulation SDC6 demonstrated a greater percentage of inhibition than the purified drug and super disintegrant, and the results were statistically significant using one-way ANOVA followed by the Bonferroni test. Conclusions. The solid dispersions were prepared with β-cyclodextrin, and skimmed milk powder improved the solubility of the poorly water-soluble fenoprofen calcium dihydrate. In vitro dissolution experiments of fenoprofen calcium dihydrate mouth dissolving tablets and controlled tablets revealed significant differences

Development of Fast Release Aminated Tamarind Gum Carrier-based Solid Dispersion containing Tablets of Ketoconazole for Solubility and Dissolution Rate Enhancement

This work enhances the solubility as well as dissolution of the biopharmaceutical classification system (BCS) II drug ketoconazole (KTZ) using fast-dissolving tablets that contain solid aminated tamarind gum (ATG). In the first stage amination of the tamarind gum was done to form ATG and which was confirmed by the presence of characteristic peaks using Fourier-transform infrared spectroscopy (FTIR). DSC-TGA analysis showed a weight loss with 3.91% at 100℃, 54.42% loss at 235 to 425℃ and 90% at 485℃. The proton nuclear magnetic resonance (1H-NMR) showed all resonance peaks observed in ATG. The XRD analysis of ATG confirmed the amorphous nature of the material. The second phase involved developing KTZ-loaded solid dispersion (SD) using the kneading process. KTZ SD showed drug content of 94.55 to 97.21%. SD of KTZ manufactured with TG showed 2.55 to 23.82-fold solubility enhancement in water while in case of SD with ATG showed 28.51 to 33.19-fold solubility enhancement. KTZ had a 32% dissolution rate in the pure drug sample, but the SD5 formulation showed a complete release of solid dispersion in 120 minutes. In FTIR, the disappearance of the peak signifies the production of solid dispersion and the drug’s transformation from a crystalline to an amorphous state. Powder X-ray diffraction (PXRD) analysis of solid dispersions reveals a notable decline in crystallinity, as shown by the removal of strong, distinguishing peaks. The scanning electron microscope (SEM) analysis confirmed the successful development of the SD in which KTZ was observed to be dispersed in a polymeric carrier. Optimized KTZ-loaded SD were utilized in fast-dissolving tablets as the third phase. When compared to the drug release achieved from solid dispersions, it was discovered that the dissolving characteristics of all formulation batches were improved.

Supercritical fluid technology as a strategy for nifedipine solid dispersions formulation: In vitro and in vivo evaluation

Supercritical fluid technology (SFT) is an insufficiently investigated approach for the production of solid dispersions, it is environmentally acceptable and has a high potential for application in the pharmaceutical industry. The aim of this work was to formulate and characterize nifedipine solid dispersions (SDs) produced by the SFT and compare the results with ones obtained by the classical solvent based kneading method. The following in vitro tests were conducted: assay and yield, solvent residues, solid state characterization (FTIR, DSC, XRD), flowability, hygroscopicity, solubility, dissolution and stability. Additionally, bioavailability was examined on an animal model (Wistar rats). The formulation selection for in vivo study was performed using the multilevel categoric experimental design and the health risk assessment. Solid state characterization revealed that formulation obtained by the SFT method and higher ratio of polymer (1:5) have had nifedipine in completely amorphous form. Polymer ratio and method of SDs preparation do influence the investigation characteristics. Dissolution rate was fastest in SDs prepared by the SFT and higher polymer ration (1:5). In vivo data of selected SDs prepared by the kneading (ratio 1:1) and the SFT (ratio 1:5) showed alteration in pharmacokinetic profile after i.v. and p.o. application.

Optimization and Production of Aceclofenac-Loaded Microfiber Solid Dispersion by Centrifugal Spinning.

Aceclofenac-loaded polyvinylpyrrolidone fiber-based amorphous solid dispersion was produced successfully by centrifugal spinning. The solution concentration and rotational speed were optimized to produce the fiber-based drug carrier system, with a determined production rate of 12.7 g/h dry solid fibers. The obtained fibers were bead-free and smooth-surfaced with an average diameter of 7.5 ± 2.5 μm. Gas chromatographic determinations revealed that ethanol, as a residual solvent, was well below the regulatory limit of 0.5%. Differential scanning calorimetric investigation and infrared spectroscopic measurements were used to track the physicochemical changes that intervene during fiber formation in the solid state. The results revealed that the rapid evaporation of the solvent was accompanied by a probable crystalline to amorphous transition of the active substance during centrifugal spinning. In vitro dissolution studies revealed an instantaneous disintegration of the fibrous structure and a rapid release of the active substance, with the microfibrous webs greatly outperforming the crystalline active substance, especially in the early time-points. This implies that centrifugal spinning offers a viable scale-up production process to prepare drug-loaded fiber-based solid dispersions.

Micro-Injection Moulding of PEO/PCL Blend–Based Matrices for Extended Oral Delivery of Fenbendazole

Fenbendazole (FBZ) is a broad-spectrum anthelmintic administered orally to ruminants; nevertheless, its poor water solubility has been the main limitation to reaching satisfactory and sustained levels at the site of the target parasites. Hence, the exploitation of hot-melt extrusion (HME) and micro-injection moulding (µIM) for the manufacturing of extended-release tablets of plasticised solid dispersions of poly(ethylene oxide) (PEO)/polycaprolactone (PCL) and FBZ was investigated due to their unique suitability for semi-continuous manufacturing of pharmaceutical oral solid dosage forms. High-performance liquid chromatography (HPLC) analysis demonstrated a consistent and uniform drug content in the tablets. Thermal analysis using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) suggested the amorphous state of the active ingredient, which was endorsed by powder X-ray diffraction spectroscopy (pXRD). Fourier transform infrared spectroscopy (FTIR) analysis did not display any new peak indicative of either a chemical interaction or degradation. Scanning electron microscopy (SEM) images showed smoother surfaces and broader pores as we increased the PCL content. Electron-dispersive X-ray spectroscopy (EDX) revealed that the drug was homogeneously distributed within the polymeric matrices. Drug release studies attested that all moulded tablets of amorphous solid dispersions improved the drug solubility, with the PEO/PCL blend-based matrices showing drug release by Korsmeyer-Peppas kinetics. Thus, HME coupled with µIM proved to be a promising approach towards a continuous automated manufacturing process for the production of oral solid dispersions of benzimidazole anthelmintics to grazing cattle.

Investigating the physicochemical properties of solid dispersions based on semicrystalline carriers: A case study with ketoprofen

Hydrophilic semicrystalline carriers represent an alternative to amorphous polymers due to their low melting temperature, useful for the production of solid dispersions (SDs) by melting-based technologies. This research aims to compare SDs of ketoprofen (KET) and three different semicrystalline carriers (PEG, Poloxamer and Gelucire) regarding miscibility, phase behavior, molecular interactions and stability. KET was chosen owing to its low solubility and high glass forming ability. Estimation of drug-excipient miscibility was performed by Flory-Huggins theory. Negative Gibbs free energy indicated a spontaneous mixing of KET with the three carriers and miscibility in the order PEG > Poloxamer > Gelucire. SDs up to 40 % w/w of drug were produced by melting process at a temperature below KET melting point. Characterization of SDs was performed by differential scanning calorimetry, polarized light microscopy and powder X-ray diffraction. In case of PEG and Poloxamer, the drug incorporation did not affect carrier crystallinity, while KET was in the amorphous state. Differently, KET retarded the crystallization of Gelucire and at high drug loadings the SDs were amorphous and semisolid. FT-IR analysis revealed a strong interaction between KET and the three carriers. Finally, PEG-based SDs above 20 % KET loading displayed drug crystallization after 6 months of storage; while Poloxamer and Gelucire-based SDs showed KET crystallization only at 40 % KET. Due to its less hydrophilic character and limited water uptake, Gelucire showed the best stability among the three excipients.

Formulation and Evaluation of Obeticholic Acid Solid Dispersion Tablet

Obeticholic acid is a farnoside X receptor agonist that was recently licenced by the US Food and Drug Administration. In a solvent, solubility is lower, therefore it is necessary to improve solubility. Solid dispersion is one of the most effective methods for increasing Obeticholic acid's solubility. Solid dispersion can be prepared in a variety of ways. Fusion (Hot Melting) is one of the most straightforward and cost-effective methods for producing solid dispersion. Poloxamer is one of the finest polymers for solid dispersion production. Poloxamer 188 and Poloxamer 407 are widely accessible. Above solid dispersion is made using the fusion or hot melting procedure. The solubility of the prepared solid dispersion has increased to 0.347 mg/ml. In comparison to the polymer combination, which has a drug release rate of 99.63 percent, the percent drug release is also superior. Precompression settings were found to be within a reasonable range. Post compression parameters such as Hardness, Friability, Uniformity of weight, content uniformity are in standard range. F7 formulation shows 99.63 ± 0.19 in 60 minutes of time. Phosphate buffer 7.4 is used for dissolution test apparatus. All result parameter shows that prepared solid dispersion of Obeticholic acid by using poloxamer gives improved solubility and increased drug release.

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.

Effect of milling time on the release of Meloxicam-HPMC milled mixture

In this piece of work we investigated the effect of milling time on the release of meloxicam from the meloxicam-HPMC mixture. Meloxicam, a well-known non-steroidal anti-inflammatory drug, is poorly water-soluble drug which affects its bioavailability. For this reason many studies were performed to ensure its solubility. Milling of the pharmaceutical active ingredient nowadays pays researchers attention in order enhance the drug solubility via reduction particles size and/ or through amorphisation. Recently, milling of the drug is consider as a green area for the production of amorphous solid dispersion due to the avoidance of solvent usage and heat. Polymers which are water soluble such as HPMC were used in the production of amorphous material due to its stabilisation and solubilisation effect. In this work different milling time 10, 20, 30, 40 and 60 minutes were chosen for meloxicam-HPMC mixture. Then the dissolution study was performed using phosphate buffer at pH 7.4 for 120 minutes dissolution time. The effect of HPMC on the release was studied. Our results showed that the % of the drug release from meloxicam-HPMC mixture increased with increasing milling time. Furthermore, the release of meloxicam in the presence of polymer was higher than release of the drug alone. This could be attributed to the reduction in the particle size or due to the appearance of amorphous form after milling which increased with increasing milling time. Polymer enhances drug release by its solubilising and stabilising effect. This pre-formulation study is important for pharmaceutical industry to formulate this drug with easy and low cost method of preparation.

Facile preparation of solid dispersions by dissolving drugs in N-vinyl-2-pyrrolidone and photopolymerization

Drug solid dispersions improve the dissolution of drugs in aqueous media for enhancement of oral bioavailability. The current preparation methods of drug solid dispersions mainly involve the evaporation of solvents or the melting of drugs and matrix. Here, we create a new and simple method for the preparation of drug solid dispersions by dissolving drugs in N-vinyl-2-pyrrolidone (NVP) and then NVP photopolymerization. A variety of drugs were explored to find whether they were suitable for this method and only some of them were soluble in NVP and formed transparent and hard solid dispersions, including fluconazole, ketoconazole, bifonazole, miconazole nitrate, sulfamethoxazole, aspirin, ibuprofen and artesunate. The formation of photocuring solid dispersions was highly related to the free radical scavenging function of drugs. Those drugs with strong free radical scavenging capability, including curcumin, resveratrol, quercetin, genistein, puerarin, nicergoline, olanzapine, indomethacin, did not form solid dispersions. They scavenged 2,2-diphenyl-1-picrylhydrazyl free radicals, which was demonstrated by ultraviolet spectrometry and electron spin resonance. The scavenging of free radicals stopped the chain polymerization of NVP. The Fourier transform infrared spectra, X-ray diffraction and differential scanning calorimetry of ibuprofen solid dispersions and artesunate solid dispersions showed the molecularly miscible state of the drugs and the hydrogen bonding between the drugs and polyvinyl pyrrolidone. The NVP-based solid dispersions of the two drugs had faster and more complete dissolution than their traditional solid dispersions. The NVP photopolymerization-based solid dispersion method provides a new choice for the production of solid dispersions in the research and industrial fields.

Development of novel darunavir amorphous solid dispersions with mesoporous carriers

The aim of this work was to compare mesoporous carriers based on silica and magnesium aluminosilicate in the amorphous solid dispersion production. Darunavir has been selected as an active pharmaceutical ingredient that is classified as a Class 2 BCS substance and exists in two commercially available forms: crystalline ethanolate and amorphous. In the course of the study, the conditions for the preparation of amorphous samples with the selected carriers were evaluated within the framework of the most common methods for obtaining solid dispersions - hot-melt extrusion, solvent wetting, and spray drying. It was determined that the obtained dispersion properties almost completely repeat the properties of the corresponding carriers. The resulting dispersions were examined in a dissolution test and the best ones was used to formulate tablets, which were studied in an in vitro dissolution test with the original Prezista. The proposed tablet formulation showed improved dissolution compared to the original one. It was also found that silica supports have a greater positive contribution to darunavir dissolution - both ethanolate or amorphous forms.

Central composite designed solid dispersion for dissolution enhancement of fluvastatin sodium by kneading technique.

Aim: This research is focused on enhancing aqueous solubility and dissolution of fluvastatin sodium (FSS) through solid dispersion (FSS-SD) production using polyethylene glycol 6000 and polyvinyl pyrollidone K-30 by kneading technique. Methodology & results: Central composite design explored the influence of polyethylene glycol 6000 and polyvinyl pyrollidone K-30 on T50% and Q90. The aqueous saturation solubility of FSS (8.7±1.12μg/ml) was amplified 20-fold in FSS-SD (179±4.16μg/ml). Cumulative drug release from FSS and optimized FSS-SD were 27.49 and 87.4% within 90min, respectively. Conclusion: FSS-SD production using kneading technique offers great prospective in maximizing FSS's solubility and dissolution.

Tablet Development for a Hydroscopic Drug Using Solid Dispersion

Introduction. Traumatic brain injury is a damage to the brain from an external mechanical force, possibly leading to permanent or temporary impairment of cognitive, physical, and psychosocial functions. It is a leading cause of death and disability among children and young adults. In connection with the above, the objective of developing new, more effective nootropic and antiasthenic drugs in the framework of restorative neurology is considered as one of the priority tasks of medical science in Russia.Aim. Development the composition and technology of tablets containing a hygroscopic substance using solid dispersions.Materials and methods. The pharmaceutical substance of a diethylaminoethanol derivative having antihypoxic, neuroprotective, adaptogenic and antioxidant effects is a hygroscopic powder. PEG 6000 was chosen as a matrix for solid dispersion production. Solid dispersions were obtained by high shear mixing and hot-melt extrusion. The technological properties of granulate and the quality indicators of the tablets were determined according to the methods described in the State Pharmacopoeia of the Russian Federation (14th edition).Results and discussion. The lactose mixed with the DEAE-PEG composition alloy improve the technological properties of granulate.Conclusion. A decrease water-absorbing ability of DEAE was achieved using PEG 6000 as a matrix carrier. The increase PEG content did not lead to a significant change in the kinetics of the release of DEAE from tablets.

Enhancement of solubility of Metaclopramide using solid dispersion technique with different carriers (HPβCD, PVP K-30)

Modern drug discovery has led to the development of drug molecules that exhibit high lipophilicity and poor water solubility, which leads to problematic bioavailability. Approaches have thus been made to enhance dissolution of poorly water soluble drugs through modifications and creation of specific formulations. Metaclopramide is an antiemetic and gastroprokinetic agent, commonly used to treat nausea and vomiting. It is absorbed well after oral administration but a significant first pass effect in some human patients may reduce systemic bioavailability to 30%.The Metaclopramide base is thus modified from Metaclopramide hydrochloride to enhance solubility .This has been achieved by the formulating in solid dispersion since Metaclopramide is poorly water soluble. Though it is absorbed well after oral administration, a significant first pass effect in some patients reduces systemic bioavailability, which can cause adverse side effects. This solid dispersion has then been used through transdermal drug delivery. Enhancement of solubility of poorly water soluble drug by solid dispersion may be attributed to particles modified characters such as particle size reduction, improved wettability, higher porosity, decreased lattice energy, amorphous state. The main objective thus includes modification of drug Metaclopramide hydrochloride to Metaclopramide base, preparation of solid dispersion of modified Metaclopramide base drug which has poor water solubility, experimental analysis of Metaclopramide base drug and solid dispersion products with carriers.
 Keywords: solubility, Metaclopramide, solid dispersion, carriers, HPβCD, PVP K-30

Spray Congealing: An Emerging Technology to Prepare Solid Dispersions with Enhanced Oral Bioavailability of Poorly Water Soluble Drugs.

The low and variable oral bioavailability of poorly water soluble drugs remains a major concern for the pharmaceutical industry. Spray congealing is an emerging technology for the production of solid dispersion to enhance the bioavailability of poorly soluble drugs by using low-melting hydrophilic excipients. The main advantages are the absence of solvents and the possibility to obtain spherical free-flowing microparticles (MPs) by a relatively inexpensive, simple, and one-step process. This review aims to fully describe the composition, structure, physico-chemical properties, and characterization techniques of spray congealed-formulations. Moreover, the influence of these properties on the MPs performance in terms of solubility and dissolution enhancement are examined. Following, an overview of the different spray congealed systems developed to increase the oral drug bioavailability is provided, with a focus on the mechanisms underpinning the bioavailability enhancement. Finally, this work gives specific insights on the main factors to be considered for the rational formulation, manufacturing, and characterization of spray congealed solid dispersions.

FORMULATION OF ATOVAQUONE TABLET USING BIOSURFACTANT IN A TERNARY SOLID DISPERSION SYSTEM: IN VITRO AND IN VIVO EVALUATION

Objective: The goal of the present investigation was to improve the solubility and bioavailability of atovaquone tablet, using in-house biosynthesized biosurfactant in the ternary system of solid dispersion containing hydrophilic polymers with varying concentrations of biosurfactant. Atovaquone is an anti-malarial agent and belongs to biopharmaceutical classification system class IV.
 Methods: The solid dispersion of binary and ternary mixture was prepared using hydroxyl propyl methyl cellulose (HPMC) and biosurfactant respectively by a solvent evaporation method. All the atovaquone tablet formulations were prepared by incorporation of physical mixture, binary and ternary solid dispersed products with excipients by direct compression method. Pre-compression and post-compression parameters of atovaquone tablets were evaluated. In vivo bioavailability study was performed using female albino rabbits.
 Results: In vitro dissolution profile of binary and ternary system of solid dispersion products showed 8.65% and 34.64% respectively. Precompression and post-compression values of all atovaquone tablets formulations were within the specified limits. In vitro dissolution efficiency of F2 and F5 were 1.44 fold and 6.62 fold respectively, in accordance to the F1. In vivo study revealed that bioavailability of optimized formulation F5 was increased by 2.5 times and time to reach peak concentration was reduced to 1.4 h, in accordance to pure atovaquone suspension.
 Conclusion: Potential application of biosurfactant in the solid dosage form of atovaquone tablet was proved for enhanced dissolution rate and bioavailability of atovaquone for malaria treatment.

Fabrication of Hierarchical Polymeric Thin Films by Spin Coating Toward Production of Amorphous Solid Dispersion for Buccal Drug Delivery System: Preparation, Characterization, and In Vitro Release Investigations

The landscape of thin films is continuously evolving as an attractive self-administration mean to drive patient compliance. This work reports incorporation of drugs into various polymeric compositions using spin coating technology to screen amorphous solid dispersion film formation for buccal applications. Polarized light microscopy and differential scanning calorimetry were used for characterization. Physical stability was assessed after films storage at 0% RH/25°C for 6 months. Chlorpheniramine maleate, theophylline, and famotidine were used as model drugs and mixed with Opadry amb II® or Kollicoat IR®. Acryl-EZE II® or Zein was also used as surface (design I) or surface and base polymers (design II). Of all the drug-Opadry combinations, only chlorpheniramine was amorphously dispersed up to 25% (w/w). In contrast, Kollicoat IR® resulted in amorphous dispersions of all the tested drugs, suggesting that it has a better solubilization capacity. Drugs prepared in design II achieved higher in vitro release compared to respective design I, indicating that lower content of Acryl-EZE II® or Zein can decrease drug release over 3 h. It has been also revealed that Zein could improve physical stability of the aged theophylline solid-dispersed films. Release kinetics of model drugs were satisfactory when described by first-order kinetics, facilitated through anomalous transport of both diffusion and polymer swelling.

Improved Vemurafenib Dissolution and Pharmacokinetics as an Amorphous Solid Dispersion Produced by KinetiSol® Processing.

Vemurafenib is a poorly soluble, low permeability drug that has a demonstrated need for a solubility-enhanced formulation. However, conventional approaches for amorphous solid dispersion production are challenging due to the physiochemical properties of the compound. A suitable and novel method for creating an amorphous solid dispersion, known as solvent-controlled coprecipitation, was developed to make a material known as microprecipitated bulk powder (MBP). However, this approach has limitations in its processing and formulation space. In this study, it was hypothesized that vemurafenib can be processed by KinetiSol into the same amorphous formulation as MBP. The KinetiSol process utilizes high shear to rapidly process amorphous solid dispersions containing vemurafenib. Analysis of the material demonstrated that KinetiSol produced amorphous, single-phase material with acceptable chemical purity and stability. Values obtained were congruent to analysis conducted on the comparator material. However, the materials differed in particle morphology as the KinetiSol material was dense, smooth, and uniform while the MBP comparator was porous in structure and exhibited high surface area. The particles produced by KinetiSol had improved in-vitro dissolution and pharmacokinetic performance for vemurafenib compared to MBP due to slower drug nucleation and recrystallization which resulted in superior supersaturation maintenance during drug release. In the in-vivo rat pharmacokinetic study, both amorphous solid dispersions produced by KinetiSol exhibited mean AUC values at least two-fold that of MBP when dosed as a suspension. It was concluded that the KinetiSol process produced superior dosage forms containing vemurafenib with the potential for substantial reduction in patient pill burden.

Extraction Optimization and Structural and Thermal Characterization of the Antimicrobial Abietane 7α-Acetoxy-6β-hydroxyroyleanone.

The abietane 7α-acetoxy-6β-hydroxyroyleanone (AHR), obtained from plant extracts, is an attractive lead for drug development, given its known antimicrobial properties. Two basic requirements to establish any compound as a new drug are the development of a convenient extraction process and the characterization of its structural and thermal properties. In this work seven different methods were tested to optimize the extraction of AHR from Plectranthus grandidentatus. Supercritical fluid extraction (SFE) proved to be the method of choice, delivering an amount of AHR (57.351 μg·mg-1) approximately six times higher than the second best method (maceration in acetone; 9.77 μg·mg-1). Single crystal X-ray diffraction analysis of the ARH molecular and crystal structure carried out at 167 ± 2 K and 296 ± 2 K showed only a single phase, here dubbed form III (orthorhombic space group P21212), at those temperatures. The presence of two other polymorphs above room temperature was, however, evidenced by differential scanning calorimetry (DSC). The three forms are enantiotropically related, with the form III → form II and form II → form I transitions occurring at 333.5 ± 1.6 K and 352.0 ± 1.6 K, respectively. The fact that the transitions are reversible suggests that polymorphism is not likely to be an issue in the development pharmaceutical formulations based on ARH. DSC experiments also showed that the compound decomposes on melting at 500.8 ± 0.8 K. Melting should therefore be avoided if, for example, strategies to improve solubility based on the production of glassy materials or solid dispersions are considered.