Physical Stability Of Amorphous Solid Dispersions Research Articles

Impact of Poloxamer on Crystal Nucleation and Growth of Amorphous Clotrimazole.

Surfactants have been widely used as effective additives to increase the solubility and dissolution rates of amorphous solid dispersions (ASDs). However, they may also generate adverse effects on the physical stability of ASDs. In this study, we systematically investigated the impacts of poloxamer, a frequently used surfactant, on the crystallization of amorphous clotrimazole (CMZ). The added poloxamer significantly decreased the glass transition temperature (Tg) of CMZ and accelerated the growth of Form 1 and Form 2 crystals. It was found that the poloxamer had an accelerating effect on Form 1 and Form 2 but showed a larger accelerating effect on Form 1, which resulted from a combined effect of increased mobility and local phase separation at the crystal-liquid interface. Additionally, the added poloxamer exhibited different effects on nucleation of the CMZ polymorphs, which was more complicated than crystal growth. The nucleation rate of Form 1 was significantly increased by the added poloxamer, and the effect increased with increasing P407 content. However, for Form 2, nucleation was slightly decreased or unchanged. The nucleation of Form 2 may have been influenced by the Form 1 crystallization, and Form 2 converted to Form 1 during nucleation. This study increases our understanding of poloxamer and its impacts on the melt crystallization of drugs.

Moisture sorption by polymeric excipients commonly used in amorphous solid dispersions and its effect on glass transition temperature: III. Methacrylic acid-methyl methacrylate and related copolymers (Eudragit®)

Moisture sorption by polymeric carriers used in amorphous solid dispersion (ASD) plays a critical role in the physical stability of the dispersed drug as it can increase molecular mobility of drug in ASD by decreasing the glass transition temperatures (Tg) of the drug-polymer system, leading to drug crystallization. The present report describes Part III of a systematic investigation of moisture sorption by different polymers used in ASDs, where the results for four chemically different methacrylic acid-methyl methacrylate and related copolymers, namely, Eudragit® EPO, Eudragit® L100-55, Eudragit® L100, and Eudragit® S100, as the function of relative humidity (RH) are presented. Effects of moisture sorption on Tg of the polymers were also determined. Among the polymers, Eudragit® EPO is the least hygroscopic, having absorbed, for example, 1.3% w/w moisture at 25 °C/60% RH, while the three other polymers absorbed 4.7–7.5% w/w moisture at the same condition. The moisture sorption was relatively lower at 40 °C than that at 25 °C. The apparent Tg of polymers decreased with the increase in moisture content; however, Tg values remained higher than the usual storage temperature of ASD (25 °C) even at high RH, indicating that the effect of moisture sorption on the physical stability of ASD could be minimal when these polymers are used in ASDs.

The role of surfactants in preserving the stability of amorphous solid dispersions: A review

In recent years among various formulation strategies, amorphous solid dispersions (ASDs) has gained tremendous recognition for improving the solubility of poorly soluble drug substances. Among various manufacturing strategies, hot melt extrusion (HME), spray drying, kinetisol, and electrospinning are the most widely employed for developing ASDs. Despite the improving solubility and bioavailability, the stability of ASDs is the major problem haunting the pharmaceutical industries. Various factors, such as miscibility, the solubility of the drug in polymer, drug-polymer interactions, glass transition temperature, hygroscopicity, and storage conditions, determine the stability of ASDs. The poor stability of amorphous drugs also limits the drug loading capacity, resulting in an increased volume of the dosage form affecting patient compliance. Apart from the physical stability of ASDs, solution-mediated recrystallization of the drug when present in a supersaturated state is another factor affecting the quality and performance of the formulations. In recent years incorporation of surfactants to hinder solution-mediated recrystallization of drugs, thereby improving the stability and performance of ASD formulations, is being most widely investigated. The incorporation of surfactant in the HME process will also act as a plasticizer, thereby allowing the process to be carried at lower temperatures. This review article mainly focuses on the role of surfactants in ASD systems and recent advancements. Still, research is warranted to understand the mechanism of surfactants and to establish screening criteria.

A Rheological Approach for Predicting Physical Stability of Amorphous Solid Dispersions

Miscibility is an important indicator of physical stability against crystallization of amorphous solid dispersions (ASDs). Currently available methods for miscibility determination have both theoretical and practical limitations. Here we report a method of miscibility determination based on the overlap concentration, c*, which can be conveniently determined from the viscosity-composition diagram. The determined c* values for ASDs of two model drugs, celecoxib and loratadine, with four different grades of polyvinylpyrrolidone (PVP), were correlated strongly with the physical stability of ASDs. This result suggests potential application of the c* concept in guiding the design of stable high drug loaded ASD formulations. A procedure is provided to facilitate broader adoption of this methodology. The procedure is easy to apply and widely applicable for thermally stable binary drug/polymer combinations.

Evaluation of rivaroxaban amorphous solid dispersions physical stability via molecular mobility studies and molecular simulations

The present study evaluates the effect of molecular mobility and molecular interactions in the physical stability of rivaroxaban (RIV) – soluplus® (SOL) amorphous solid dispersions (ASDs). Initially, the use of Adam-Gibbs approach revealed that RIV's molecular mobility (below its glass transition temperature) is significantly reduced in the presence of SOL, while the use of ATR-FTIR spectroscopy showed the formation of hydrogen bonds (HBs) between the two ASD components, indicating that these two mechanisms can be considered as responsible for system's physical stability. Contrary to previously published reports, the utilization of ATR-FTIR spectroscopy in the present study was able to clarify, for the first time, the type of intermolecular interactions formed within the examined ASD system, while the presence of a separate drug-rich amorphous phase (significantly increasing as the content of the drug increases) was also identified. Furthermore, in order to gain an insight into the intermolecular interactions responsible for drug's amorphous phase separation, molecular dynamics (MD) simulation models were utilized as realistic representations of the actual systems. Analysis of the obtained trajectories showed that the formation of strong intermolecular HBs between RIV's secondary amide proton and its three carbonyl oxygens (originating from the οxazolidone, oxomorpholin and carboxamide part of the drug molecule) as well as the significant reduction of the available HB acceptors in SOL due to copolymer's chain shrinkage, were responsible for the formation of a separate drug-rich amorphous phase within the ASD.

Crystallization tendency of APIs possessing different thermal and glass related properties in amorphous solid dispersions.

The correlation between glass forming ability (GFA) and several thermophysical or physicochemical properties of APIs with the formation and the physical stability of amorphous solid dispersions (ASDs) was evaluated in the present study. Eight poorly water-soluble APIs belonging in different GFA classes (i.e. a) GFA Class I: Carbamazepine, CBZ, b) GFA Class II: Agomelatine, AGO, Aprepitant, APT, Rivaroxaban, RIV, and c) GFA Class III: Indomethacin, IND, Pioglitazone, PIO, Piroxixam, PIR, and Simvastatin, SIM) were tested, in addition to six commonly used matrix-carriers (namely povidone, PVP, hydroxypropyl cellulose, HPC-SL, copovidone, coPVP, Soluplus®, SOL, and gelatin) in order to prepared ASDs via film casting approach. Results using polarized light microscopy (PLM) showed a similar drug crystallization tendency from ASDs independently of their GFA classification, glass stability or glass fragility. X-ray diffraction analysis verified the formation and the physical stability of ASD (independently of GFA class) when a suitable matrix-carrier was selected (i.e. SOL for AGO, RIV and SIM, PVP for APT, CBZ and IND, coPVP for PIO and gelatin for PIR). Further attempts to correlate some physicochemical properties (i.e. component's binding affinity and miscibility) with the formation and the crystallization tendency of the prepared ASDs showed no apparent correlation in regards to the different drug GFA classes. Finally, the evaluation of molecular interactions via FTIR analysis also failed to adequately distinguish the differences in regards to the formation and the physical stability of the prepared systems.

Impact of process parameters on particle morphology and filament formation in spray dried Eudragit L100 polymer

Spray drying is one of the most broadly applicable and widely used methods of producing amorphous solid dispersions (ASDs). ASDs can improve the oral absorption of poorly water-soluble active pharmaceutical ingredients. Eudragit L100 is an appealing ASD excipient, due to its favorable impact on ASD physical stability and dissolution performance. However, spray drying Eudragit L100 can lead to high-aspect ratio filaments which reduce flowability, density and yield of the resulting powder. This negatively impacts downstream ASD performance and dosage form manufacturability. This work presents a mechanism for filament formation, which results in a particle engineering design space of key processing parameters, defined by a dimensionless parameter for assessing filament formation risk. Specifically, it was found that solution concentration, spray dryer inlet temperature and solvent volatility had the largest impact on controlling filament formation, based on their influence on the relative time scale to atomize versus droplet skinning during drying.

Use of Terahertz-Raman Spectroscopy to Determine Solubility of the Crystalline Active Pharmaceutical Ingredient in Polymeric Matrices during Hot Melt Extrusion

Polymer-based amorphous solid dispersions (ASDs) comprise one of the most promising formulation strategies devised to improve the oral bioavailability of poorly water-soluble drugs. Exploitation of such systems in marketed products has been limited because of poor understanding of physical stability. The internal disordered structure and increased free energy provide a thermodynamic driving force for phase separation and recrystallization, which can compromise therapeutic efficacy and limit product shelf life. A primary concern in the development of stable ASDs is the solubility of the drug in the polymeric carrier, but there is a scarcity of reliable analytical techniques for its determination. In this work, terahertz (THz) Raman spectroscopy was introduced as a novel empirical approach to determine the saturated solubility of crystalline active pharmaceutical ingredient (API) in polymeric matrices directly during hot melt extrusion. The solubility of a model compound, paracetamol, in two polymer systems, Affinisol 15LV (HPMC) and Plasdone S630 (copovidone), was determined by monitoring the API structural phase transitions from crystalline to amorphous as an excess of crystalline drug dissolved in the polymeric matrix. THz-Raman results enabled construction of solubility phase diagrams and highlighted significant differences in the solubilization capacity of the two polymer systems. The maximum stable API-load was 20 wt % for Affinisol 15LV and 40 wt % for Plasdone S630. Differential scanning calorimetry and XRPD studies corroborated these results. This approach has demonstrated a novel capability to provide real-time API–polymer phase equilibria data in a manufacturing relevant environment and promising potential to predict solid-state solubility and physical stability of ASDs.

Influence of mechanical and thermal energy on nifedipine amorphous solid dispersions prepared by hot melt extrusion: Preparation and physical stability

Hot melt extrusion (HME) has been used to prepare solid dispersions, especially molecularly dispersed amorphous solid dispersions (ASDs) for solubility enhancement purposes. The energy generated by the extruder in the form of mechanical and thermal output enables the dispersion and dissolution of crystalline drugs in polymeric carriers. However, the impact of this thermal and mechanical energy on ASD systems remains unclear. We selected a model ASD system containing nifedipine (NIF) and polyvinylpyrrolidone vinyl acetate (PVP/VA 64) to investigate how different types of energy input affect the preparation and physical stability of ASDs. Formulations were prepared using a Leistritz Nano-16 extruder, and we varied the screw design, barrel temperature, screw speed, and feed rate to control the mechanical and thermal energy input. Specific mechanical energy (SME) was calculated to quantitate the mechanical energy input, and the thermal energy was estimated using barrel temperature. We find that both mechanical and thermal energy inputs affect the conversion of crystalline NIF into an amorphous form, and they also affect the level of mixing and the degree of homogeneity in NIF ASDs. However, for small size extruders (e.g., Leistritz Nano-16), thermal energy is more efficient than mechanical energy in preparing NIF ASDs that have better stability.

Influence of Polymers on the Physical and Chemical Stability of Spray-dried Amorphous Solid Dispersion: Dipyridamole Degradation Induced by Enteric Polymers.

Amorphous solid dispersions (ASDs) are inherently unstable because of high internal energy. Evaluating physical and chemical stability during the process and storage is essential. Numerous researches have demonstrated how polymers influence the drug precipitation and physical stability of ASDs, while the influence of polymers on the chemical stability of ASDs is often overlooked. Therefore, this study aimed to investigate the effect of polymers on the physical and chemical stability of spray-dried ASDs using dipyridamole (DP) as a model drug. Proper polymers were selected by assessing their abilities to inhibit drug recrystallization in supersaturated solutions. HPMC E5, Soluplus®, HPMCP-55, and HPMCAS-LP were shown to be effective stabilizers. The optimized formulations were further stored at a high temperature (60°C) and high humidity (40°C, 75%RH) for 2months, and their physical and chemical stability was evaluated using polarizing optical microscopy, FTIR, HPLC, and mass spectrometry (MS). In general, crystallization was observed in all samples, which indicated the physical instability under stressed storage conditions. Also, it was noted that the polymers in ASDs rather than physical mixtures, induced a dramatic drug degradation after being exposed to a high temperature (HPMCP-55 > 80% and HPMCAS-LP > 50%) and high humidity (HPMCP-55 > 40% and HPMCAS-LP > 10%). The MS analysis further confirmed the degradation products, which might be generated from the reaction between dipyridamole and phthalic anhydride decomposed from HPMCP-55 and HPMCAS-LP. Overall, the exposure of ASDs to stressed conditions resulted in recrystallization and even the chemical degradation induced by polymers.