Multivariate Analysis of Solubility Parameters for Drug-Polymer Miscibility Assessment in Preparing Raloxifene Hydrochloride Amorphous Solid Dispersions.

The success of obtaining solid dispersions for solubility improvement invariably depends on the miscibility of the drug and polymeric carriers. This study aimed to categorize and select polymeric carriers via the classical group contribution method using the multivariate analysis of the calculated solubility parameter of RX-HCl. The total, partial, and derivate parameters for RX-HCl were calculated. The data were compared with the results of excipients (N = 36), and a hierarchical clustering analysis was further performed. Solid dispersions of selected polymers in different drug loads were produced using solvent casting and characterized via X-ray diffraction, infrared spectroscopy and scanning electron microscopy. RX-HCl presented a Hansen solubility parameter (HSP) of 23.52 MPa1/2. The exploratory analysis of HSP and relative energy difference (RED) elicited a classification for miscible (n = 11), partially miscible (n = 15), and immiscible (n = 10) combinations. The experimental validation followed by a principal component regression exhibited a significant correlation between the crystallinity reduction and calculated parameters, whereas the spectroscopic evaluation highlighted the hydrogen-bonding contribution towards amorphization. The systematic approach presented a high discrimination ability, contributing to optimal excipient selection for the obtention of solid solutions of RX-HCl.

Direct Tableting on a Continuous Manufacturing Line-Impact of Mixing Parameters, Material Densities, and Drug Load on Subsequent Process Parameters and Tablet Quality.

The continuous manufacturing (CM) of solid oral dosage forms has received increased attention in recent years and has become a leading technology in the pharmaceutical industry. A model has been developed based on process data from two design of experiments (DoEs), where the impact of the mixer process parameters, throughput (THR), hold up mass (HUM), impeller speed (IMP), and the input raw material bulk density (BDi), on the continuous process and the resulting drug product has been investigated. These statistical models revealed equations, describing process parameter interactions for optimization purposes. For the exit valve opening width (EV) at the bottom of the continuous mixer (CMT), the combination of high throughput (30 kg/h) and low impeller speed (300 rpm) resulted in optimal process conditions. Apparent bulk density of the blend (BD) within the process, fill depth (FD), and tensile strength (TS) were mainly impacted by input bulk density (BDi) of the tableting mixture, emphasizing the role of material attributes on the continuous manufacturing process. The apparent bulk density itself was, other than from the input bulk density, equally dependent from THR and IMP in opposite deflections. However, process parameters (THR and IMP) revealed a minor impact on the apparent BD compared to the input bulk density. FD was impacted mainly by THR ahead of IMP and the TS by IMP and THR to a similar extend, in opposite deflections. A simplified linear model to estimate the input bulk density revealed satisfactory prediction quality when included in the derived statistical model equations.

Corallopyronin A: antimicrobial discovery to preclinical development.

Covering: August 1984 up to January 2022Worldwide, increasing morbidity and mortality due to antibiotic-resistant microbial infections has been observed. Therefore, better prevention and control of infectious diseases, as well as appropriate use of approved antibacterial drugs are crucial. There is also an urgent need for the continuous development and supply of novel antibiotics. Thus, identifying new antibiotics and their further development is once again a priority of natural product research. The antibiotic corallopyronin A was discovered in the 1980s in the culture broth of the Myxobacterium Corallococcus coralloides and serves, in the context of this review, as a show case for the development of a naturally occurring antibiotic compound. The review demonstrates how a hard to obtain, barely water soluble and unstable compound such as corallopyronin A can be developed making use of sophisticated production and formulation approaches. Corallopyronin A is a bacterial DNA-dependent RNA polymerase inhibitor with a new target site and one of the few representatives of this class currently in preclinical development. Efficacy against Gram-positive and Gram-negative pathogens, e.g., Chlamydia trachomatis, Orientia tsutsugamushi, Staphylococcus aureus, and Wolbachia has been demonstrated. Due to its highly effective in vivo depletion of Wolbachia, which are essential endobacteria of most filarial nematode species, and its robust macrofilaricidal efficacy, corallopyronin A was selected as a preclinical candidate for the treatment of human filarial infections. This review highlights the discovery and production optimization approaches for corallopyronin A, as well as, recent preclinical efficacy results demonstrating a robust macrofilaricidal effect of the anti-Wolbachia candidate, and the solid formulation strategy which enhances the stability as well as the bioavailability of corallopyronin A.

Design, synthesis, and characterization of PROTACs targeting the androgen receptor in prostate and lung cancer models.

Although the androgen receptor (AR) is a validated target for the treatment of prostate cancer, resistance to antiandrogens necessitates the development of new therapeutic modalities. Exploiting the ubiquitin-proteasome system with proteolysis-targeting chimeras (PROTACs) has become a practical approach to degrade specific proteins and thus to extend the portfolio of small molecules used for the treatment of a broader spectrum of diseases. Herein, we present three subgroups of enzalutamide-based PROTACs in which only the exit vector was modified. By recruiting cereblon, we were able to demonstrate the potent degradation of AR in lung cancer cells. Furthermore, the initial evaluation enabled the design of an optimized PROTAC with a rigid linker that degraded AR with a DC50 value in the nanomolar range. These results provide novel AR-directed PROTACs and a clear rationale for further investigating AR involvement in lung cancer models.

ASD Formation Prior to Material Characterization as Key Parameter for Accurate Measurements and Subsequent Process Simulation for Hot-Melt Extrusion.

Process simulation facilitates scale-up of hot-melt extrusion (HME) and enhances proper understanding of the underlying critical process parameters. However, performing numeric simulations requires profound knowledge of the employed materials' properties. For example, an accurate description of the compounds' melt rheology is paramount for proper simulations. Hence, sample preparation needs to be optimized to yield results as predictive as possible. To identify the optimal preparation method for small amplitude oscillatory shear (SAOS) rheological measurements, binary mixtures of hydroxypropylmethylcellulose acetate succinate or methacrylic acid ethyl acrylate copolymer (Eudragit L100-55) together with the model drugs celecoxib and ketoconazole were prepared. The physical powder mixtures were introduced into the SAOS as a compressed tablet or a disk prepared via vacuum compression molding (VCM). Simulations with the derived parameters were conducted and compared to lab-scale extrusion trials. VCM was identified as the ideal preparation method resulting in the highest similarity between simulated and experimental values, while simulation based on conventional powder-based methods insufficiently described the HME process.

Assessment of Abrasion-Induced Visual Defects in Twin Screw Wet Granulation Using Wall Friction Measurements.

Starting point of the presented study were abrasion effects occurring during a twin screw wet granulation (TSG) process of a new chemical entity (NCE) formulation, resulting in gray spots on the final tablets. Several actions and systematic changes of equipment and process parameter settings of TSG process were conducted which reduced the visual defect rate of the tablets, i.e., gray spots on the surface, below the specification limit. To understand the rationale and mechanism behind these improvements, correlations of defect rates and wall friction measurements using a Schulze ring shear tester were evaluated. To check the suitability of the method, a broad range of wall materials as well as powder formulations at various moisture levels were investigated with regard to their wall friction angle. As differences in wall friction angle could be detected, further experiments were conducted using wall material samples made out of different screw materials for TSG. Evaluation of these screw wall material samples gave first hints, which screw materials should be preferred in regard of friction for TSG process. In the finally presented case study, wall friction measurements were performed using the above mentioned NCE formulation with known abrasion issues at TSG processing. The results confirmed that changes which led to a reduced visual defect rate of tablets correlated with a decreased wall friction angle. The results suggest wall friction measurements as a potent tool for equipment selection and establishment of a suitable process window prior to conducting TSG experiments.

Transformation of Ritonavir Nanocrystal Suspensions into a Redispersible Drug Product via Vacuum Drum Drying.

The present study explored vacuum drum drying (VDD) as potential drying technique for the solidification of crystalline ritonavir nanosuspensions prepared by wet-ball milling. In detail, the impact of drying protectants (mannitol, lactose, trehalose) added to the ritonavir nanosuspension was assessed in dependence of the drum temperature with respect to processibility via VDD, resulting intermediate powder properties, remaining nanoparticulate redispersibility and crystallinity. A clear impact of the glass transition temperature (Tg) of the drying protectant on the redispersibility/crystallinity of the VDD intermediate was observed. Increased Tg of the drying protectant was associated with improved redispersibility/crystallinity at a defined drum temperature. Consequently, the high Tg-substance trehalose and lactose showed a better performance than mannitol at higher drum temperatures. However, the processability and related powder properties were not in accordance with this observation. Mannitol containing formulations showed superior processibility to those containing trehalose/lactose. Moreover, the impact of the tableting and encapsulation process on the redispersibility of the VDD intermediate was studied for a selected formulation. Neither process demonstrated a negative impact on redispersibility. In conclusion, vacuum drum drying is a promising drying technique for the solidification of nanosuspensions to result in dried powder still containing ritonavir nanoparticles while demonstrating acceptable to good downstream processibility to tablets/capsules.

Shellac- a natural carrier for colon targeting of indomethacin using hot melt extrusion.

Indomethacin (IND) is one of the supporting drug candidates for colonic targeting but it belongs to BCS class II category presenting a challenge in optimal targeting at the colonic site. To overcome this challenge, we sought to prepare a pH-dependent soluble ternary solid dispersion (SD) of IND of improved solubility and dissolution rate at the colon without the need for a coating. The current study focuses on the preparation of binary SDs of API (IND) with shellac (SSB 55) and Eudragit FS 100 (EFS) and ternary mixtures of IND, SSB 55 together with a new grade of HPMC (A15). Respective SDs were prepared via HME to achieve gastric protection and improved dissolution performance including maintenance of supersaturation. The SDs were characterized and tested for in-vitro dissolution performance using a pH shift dissolution method from 1.1, 5.5, 6.8, and 7.4. A ternary extrudate of IND, SSB 55, and A15 showed improved protection below pH 5.5 with a complete release of 99.5% at pH 7.4 compared to IND neat and binary extrudates from IND-A15, IND-SSB 55, and IND-EFS. It was attributed to an increased level of intermolecular interaction confirmed by ATR-IR and was studied for stability. It was found that in a ternary mixture containing IND, A15 and SSB 55 an increased hydrogen bonding interaction is present, which resulted in improved dissolution performance compared to binary mixtures. Therefore, ternary SDs proved to be a promising concept for future development of colon targeting of poorly soluble drugs.

Influence of Particle Size and Drug Load on Amorphous Solid Dispersions Containing pH-Dependent Soluble Polymers and the Weak Base Ketoconazole.

Among the great number of poorly soluble drugs in pharmaceutical development, most of them are weak bases. Typically, they readily dissolve in an acidic environment but are prone to precipitation at elevated pH. This was aimed to be counteracted by the preparation of amorphous solid dispersions (ASDs) using the pH-dependent soluble polymers methacrylic acid ethylacrylate copolymer (Eudragit L100-55) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) via hot-melt extrusion. The hot-melt extruded ASDs were of amorphous nature and single phased with the presence of specific interactions between drug and polymer as revealed by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FT-IR). The ASDs were milled and classified into six particle size fractions. We investigated the influence of particle size, drug load, and polymer type on the dissolution performance. The best dissolution performance was achieved for the ASD made from Eudragit L100-55 at a drug load of 10%, whereby the dissolution rate was inversely proportional to the particle size. Within a pH-shift dissolution experiment (from pH 1 to pH 6.8), amorphous-amorphous phase separation occurred as a result of exposure to acidic medium which caused markedly reduced dissolution rates at subsequent higher pH values. Phase separation could be prevented by using enteric capsules (Vcaps Enteric®), which provided optimal dissolution profiles for the Eudragit L100-55 ASD at a drug load of 10%.

Immediate-Release Formulations Produced via Twin-Screw Melt Granulation: Systematic Evaluation of the Addition of Disintegrants.

The current study evaluated the effect of location and amount of various superdisintegrants on the properties of tablets made by twin-screw melt granulation (TSMG). Sodium-croscarmellose (CCS), crospovidone (CPV), and sodium starch glycolate (SSG) were used in various proportions intra- and extra-granular. Tabletability, compactibility, compressibility as well as friability, disintegration, and dissolution performance were assessed. The extra-granular addition resulted in the fasted disintegration and dissolution. CPV performed superior to CCS and SSG. Even if the solid fraction (SF) of the granules was lower for CPV, only a minor decrease in tabletability was observed, due to the high plastic deformation of the melt granules. The intra-granular addition of CPV resulted in a more prolonged dissolution profile, which could be correlated to a loss in porosity during tableting. The 100% intra-granular addition of the CPV resulted in a distinct decrease of the disintegration efficiency, whereas the performance of SSG was unaffected by the granulation process. CCS was not suitable to be used for the production of an immediate-release formulation, when added in total proportion into the granulation phase, but its efficiency was less impaired compared to CPV. Shortest disintegration (78 s) and dissolution (Q80: 4.2 min) was achieved with CPV extra-granular. Using CPV and CCS intra-granular resulted in increased disintegration time and Q80. However, at a higher level of appx. 500 s and appx. 15 min, only SSG showed a process and location independent disintegration and dissolution performance.

Tricalcium citrate - a new brittle tableting excipient for direct compression and dry granulation with enormous hardness yield.

OBJECTIVES: Tricalcium citrate (TCC) was characterized as a tableting excipient for direct compression (DC) and dry granulation (DG). SIGNIFICANCE: Brittle materials usually lead to tablets of inferior mechanical strength compared to plastic deforming materials. A brittle material exhibiting a high tabletability with the ability to retain that behavior during recompression would represent a valuable alternative to the commonly used microcrystalline cellulose. METHODS: Tablets of TCC and other common fillers were directly compressed for the purpose of compression analysis including Heckel analysis, speed dependency, and lubricant sensitivity. DG by roller compaction of TCC was first simulated via briquetting and experiments were subsequently repeated on a roller compactor. RESULTS: TCC appears as an excellent flowing powder of large agglomerates consisting of lower micron to submicron platelets. Despite the brittle deformation mechanism identified in the Heckel analysis, TCC demonstrated a very high mechanical strength up to 11 MPa in conjunction with an astonishingly low solid fraction of 0.85 at a compression pressure of 400 MPa. This was seen along with hardly any speed and lubricant sensitivity. Nevertheless, disintegration time was very short. TCC tablets suffered only a little from the re-compression: a slight loss in tensile strength of 1-2 MPa was observed for granules produced via roller compaction. CONCLUSIONS: TCC was found to be suitable for DC as a predominantly brittle deforming filler, nevertheless demonstrating an enormous hardness yield while being independent of lubrication and tableting speed. TCC furthermore retained enough bonding capacity after DG to maintain this pronounced tabletability.

Development and Performance of a Highly Sensitive Model Formulation Based on Torasemide to Enhance Hot-Melt Extrusion Process Understanding and Process Development.

The aim of this work was to investigate the use of torasemide as a highly sensitive indicator substance and to develop a formulation thereof for establishing quantitative relationships between hot-melt extrusion process conditions and critical quality attributes (CQAs). Using solid-state characterization techniques and a 10 mm lab-scale co-rotating twin-screw extruder, we studied torasemide in a Soluplus® (SOL)-polyethylene glycol 1500 (PEG 1500) matrix, and developed and characterized a formulation which was used as a process indicator to study thermal- and hydrolysis-induced degradation, as well as residual crystallinity. We found that torasemide first dissolved into the matrix and then degraded. Based on this mechanism, extrudates with measurable levels of degradation and residual crystallinity were produced, depending strongly on the main barrel and die temperature and residence time applied. In addition, we found that 10% w/w PEG 1500 as plasticizer resulted in the widest operating space with the widest range of measurable residual crystallinity and degradant levels. Torasemide as an indicator substance behaves like a challenging-to-process API, only with higher sensitivity and more pronounced effects, e.g., degradation and residual crystallinity. Application of a model formulation containing torasemide will enhance the understanding of the dynamic environment inside an extruder and elucidate the cumulative thermal and hydrolysis effects of the extrusion process. The use of such a formulation will also facilitate rational process development and scaling by establishing clear links between process conditions and CQAs.

Hot Melt Extrusion for Sustained Protein Release: Matrix Erosion and In Vitro Release of PLGA-Based Implants.

The design of biodegradable implants for sustained release of proteins is a complex challenge optimizing protein polymer interaction in combination with a mini-scale process which is predictive for production. The process of hot melt extrusion (HME) was therefore conducted on 5- and 9-mm mini-scale twin screw extruders. Poly(lactic-co-glycolic acid) (PLGA) implants were characterized for their erosion properties and the in vitro release of the embedded protein (bovine serum albumin, BSA). The release of acidic monomers as well as other parameters (pH value, mass loss) during 16 weeks indicated a delayed onset of matrix erosion in week 3. BSA-loaded implants released 17.0% glycolic and 5.9% lactic acid after a 2-week lag time. Following a low burst release (3.7% BSA), sustained protein release started in week 4. Storage under stress conditions (30°C, 75% rH) revealed a shift of erosion onset of 1 week (BSA-loaded implants: 26.9% glycolic and 9.3% lactic acid). Coherent with the changed erosion profiles, an influence on the protein release was observed. Confocal laser scanning and Raman microscopy showed a homogenous protein distribution throughout the matrix after extrusion and during release studies. Raman spectra indicated a conformational change of the protein structure which could be one reason for incomplete protein release. The study underlined the suitability of the HME process to obtain a solid dispersion of protein inside a polymeric matrix providing sustained protein release. However, the incomplete protein release and the impact by storage conditions require thorough characterization and understanding of erosion and release mechanisms.

High loading of lipophilic compounds in mesoporous silica for improved solubility and dissolution performance.

Loading poorly soluble active pharmaceutical ingredients (API) into mesoporous silica can enable API stabilization in non-crystalline form, which leads to improved dissolution. This is particularly beneficial for highly lipophilic APIs (log D7.4 > 8) as these drugs often exhibit limited solubility in dispersion forming carrier polymers, resulting in low drug load and reduced solid state stability. To overcome this challenge, we loaded the highly lipophilic natural products coenzyme Q10 (CoQ10) and astaxanthin (ASX), as well as the synthetic APIs probucol (PB) and lumefantrine (LU) into the mesoporous silica carriers Syloid® XDP 3050 and Silsol® 6035. All formulations were physically stable in their non-crystalline form and drug loads of up to 50 % were achieved. At increasing drug loads, a marked increase in equilibrium solubility of the active ingredients in biorelevant medium was detected, leading to improved performance during biorelevant biphasic dissolution studies (BiPHa + ). Particularly the natural products CoQ10 and ASX showed substantial benefits from being loaded into mesoporous carrier particles and clearly outperformed currently available commercial formulations. Performance differences between the model compounds could be explained by in silico calculations of the mixing enthalpy for drug and silica in combination with an experimental chromatographic method to estimate molecular interactions.

Evaluation of Printability of PVA-Based Tablets from Powder and Assessment of Critical Rheological Parameters.

Fused deposition modeling (FDM) is a rather new technology in the production of personalized dosage forms. The melting and printing of polymer-active pharmaceutical ingredient (API)-mixtures can be used to produce oral dosage forms with different dosage as well as release behavior. This process is utilized to increase the bioavailability of pharmaceutically relevant active ingredients that are poorly soluble in physiological medium by transforming them into solid amorphous dispersions (ASD). The release from such ASDs is expected to be faster and higher compared to the raw materials and thus enhance bioavailability. Printing directly from powder while forming ASDs from loperamide in Polyvinylalcohol was realized. Different techniques such as a change in infill and the incorporation of sorbitol as a plastisizer to change release patterns as well as a non-destructive way for the determination of API distribution were shown. By measuring the melt viscosities of the mixtures printed, a rheological model for the printer used is proposed.

Mesoporous Silica as an Alternative Vehicle to Overcome Solubility Limitations.

Toxicological studies are a part of the drug development process and the preclinical stages, for which suitable vehicles ensuring easy and safe administration are crucial. However, poor aqueous solubility of drugs complicates vehicle screening for oral administration since non-aqueous solvents are often not tolerable. In the case of the anti-infective corallopyronin A, currently undergoing preclinical investigation for filarial nematode and bacterial infections, commonly used vehicles such as polyethylene glycol 200, aqueous solutions combined with cosolvents or solubilizers, or aqueous suspension have failed due to insufficient tolerability, solubility, or the generation of a non-homogeneous suspension. To this end, the aim of the study was to establish an alternative approach which offers suitable tolerability, dissolution, and ease of handling. Thus, a corallopyronin A-mesoporous silica formulation was successfully processed and tested in a seven-day toxicology study focused on Beagle dogs, including a toxicokinetic investigation on day one. Sufficient tolerability was confirmed by the vehicle control group. The vehicle enabled high-dose levels resulting in a low-, middle-, and high-dose of 150, 450, and 750 mg/kg. Overall, it was possible to achieve high plasma concentrations and exposures, leading to a valuable outcome of the toxicology study and establishing mesoporous silica as a valuable contender for challenging drug candidates.

Micro-Scale Vacuum Compression Molding as a Predictive Screening Tool of Protein Integrity for Potential Hot-Melt Extrusion Processes.

Hot-melt extrusion (HME) is used for the production of solid protein formulations mainly for two reasons: increased protein stability in solid state and/or long-term release systems (e.g., protein-loaded implants). However, HME requires considerable amounts of material even at small-scale (>2 g batch size). In this study, we introduced vacuum compression molding (VCM) as a predictive screening tool of protein stability for potential HME processing. The focus was to identify appropriate polymeric matrices prior to extrusion and evaluation of protein stability after thermal stress using only a few milligrams of protein. The protein stability of lysozyme, BSA, and human insulin embedded in PEG 20,000, PLGA, or EVA by VCM was investigated by DSC, FT-IR, and SEC. The results from the protein-loaded discs provided important insights into the solid-state stabilizing mechanisms of protein candidates. We demonstrated the successful application of VCM for a set of proteins and polymers, showing, in particular, a high potential for EVA as a polymeric matrix for solid-state stabilization of proteins and the production of extended-release dosage forms. Stable protein-polymer mixtures with sufficient protein stability after VCM could be then introduced to a combination of thermal and shear stress by HME and further investigated with regard to their process-related protein stability.

Advanced In Vivo Prediction by Introducing Biphasic Dissolution Data into PBPK Models.

Coupling biorelevant in vitro dissolution with in silico physiological-based pharmacokinetic (PBPK) tools represents a promising method to describe and predict the in vivo performance of drug candidates in formulation development including non-passive transport, prodrug activation, and first-pass metabolism. The objective of the present study was to assess the predictability of human pharmacokinetics by using biphasic dissolution results obtained with the previously established BiPHa+ assay and PBPK tools. For six commercial drug products, formulated by different enabling technologies, the respective organic partitioning profiles were processed with two PBPK in silico modeling tools, namely PK-Sim and GastroPlus®, similar to extended-release dissolution profiles. Thus, a mechanistic dissolution/precipitation model of the assessed drug products was not required. The developed elimination/distribution models were used to simulate the pharmacokinetics of the evaluated drug products and compared with available human data. In essence, an in vitro to in vivo extrapolation (IVIVE) was successfully developed. Organic partitioning profiles obtained from the BiPHa+ dissolution analysis enabled highly accurate predictions of the pharmacokinetic behavior of the investigated drug products. In addition, PBPK models of (pro-)drugs with pronounced first-pass metabolism enabled adjustment of the solely passive diffusion predicting organic partitioning profiles, and increased prediction accuracy further.

Amorphous Solid Dispersions Layered onto Pellets-An Alternative to Spray Drying?

Spray drying is one of the most frequently used solvent-based processes for manufacturing amorphous solid dispersions (ASDs). However, the resulting fine powders usually require further downstream processing when intended for solid oral dosage forms. In this study, we compare properties and performance of spray-dried ASDs with ASDs coated onto neutral starter pellets in mini-scale. We successfully prepared binary ASDs with a drug load of 20% Ketoconazole (KCZ) or Loratadine (LRD) as weakly basic model drugs and hydroxypropyl-methyl-cellulose acetate succinate or methacrylic acid ethacrylate copolymer as pH-dependent soluble polymers. All KCZ/ and LRD/polymer mixtures formed single-phased ASDs, as indicated by differential scanning calorimetry, X-ray powder diffraction and infrared spectroscopy. All ASDs showed physical stability for 6 months at 25 °C/65% rH and 40 °C/0% rH. Normalized to their initial surface area available to the dissolution medium, all ASDs showed a linear relationship of surface area and solubility enhancement, both in terms of supersaturation of solubility and initial dissolution rate, regardless of the manufacturing process. With similar performance and stability, processing of ASD pellets showed the advantages of a superior yield (>98%), ready to use for subsequent processing into multiple unit pellet systems. Therefore, ASD-layered pellets are an attractive alternative in ASD-formulation, especially in early formulation development at limited availability of drug substance.

Phase homogeneity in ternary amorphous solid dispersions and its impact on solubility, dissolution and supersaturation - Influence of processing and hydroxypropyl cellulose grade.

As performance of ternary amorphous solid dispersions (ASDs) depends on the solid-state characteristics and polymer mixing, a comprehensive understanding of synergistic interactions between the polymers in regard of dissolution enhancement of poorly soluble drugs and subsequent supersaturation stabilization is necessary. By choosing hot-melt extrusion (HME) and vacuum compression molding (VCM) as preparation techniques, we manipulated the phase behavior of ternary efavirenz (EFV) ASDs, comprising of either hydroxypropyl cellulose (HPC)-SSL or HPC-UL in combination with Eudragit® L 100-55 (EL 100-55) (50:50 polymer ratio), leading to single-phased (HME) and heterogeneous ASDs (VCM). Due to higher kinetic solid-state solubility of EFV in HPC polymers compared to EL 100-55, we visualized higher drug distribution into HPC-rich phases of the phase-separated ternary VCM ASDs via confocal Raman microscopy. Additionally, we observed differences in the extent of phase-separation in dependence on the selected HPC grade. As HPC-UL exhibited decisive lower melt viscosity than HPC-SSL, formation of partially miscible phases between HPC-UL and EL 100-55 was facilitated. Consequently, as homogeneously mixed polymer phases were required for optimal extent of solubility improvement, the manufacturing-dependent differences in dissolution performances were smaller using HPC-UL, instead of HPC-SSL, i.e. using HPC-UL was less demanding on shear stress provided by the process.