The evaluation of drug–polymer miscibility in the early phase of drug development is essential to ensure successful amorphous solid dispersion (ASD) manufacturing. This work investigates the comparison of thermodynamic models, conventional experimental screening methods (solvent casting, quench cooling), and a novel atomization screening device based on their ability to predict drug–polymer miscibility, solid state properties (Tg value and width), and adequate polymer selection during the development of spray-dried amorphous solid dispersions (SDASDs). Binary ASDs of four drugs and seven polymers were produced at 20:80, 40:60, 60:40, and 80:20 (w/w). Samples were systematically analyzed using modulated differential scanning calorimetry (mDSC) and X-ray powder diffraction (XRPD). Principal component analysis (PCA) was used to qualitatively assess the predictability of screening methods with regards to SDASD development. Poor correlation was found between theoretical models and experimentally-obtained results. Additionally, the limited ability of usual screening methods to predict the miscibility of SDASDs did not guarantee the appropriate selection of lead excipient for the manufacturing of robust SDASDs. Contrary to standard approaches, our novel screening device allowed the selection of optimal polymer and drug loading and established insight into the final properties and performance of SDASDs at an early stage, therefore enabling the optimization of the scaled-up late-stage development.
Spray-drying is an increasingly popular technology for the production of amorphous solid dispersions (ASDs) in the pharmaceutical industry that is used in the early evaluation and industrial production of formulations. Efficient screening of ASD in the earliest phase of drug development is therefore critical. A novel miniaturized atomization equipment for screening spray-dried solid dispersions (SDSDs) in early formulation and process development was developed. An in-depth comparison between the equipment/process parameters and performance of our novel screening device and a laboratory Büchi B290 mini spray-dryer was performed. Equipment qualification was conducted by comparing the particle/powder attributes, i.e., miscibility/solid state, residual solvent, and morphological properties of binary SDSDs of itraconazole prepared at both screening and laboratory scales. The operating mode of the miniaturized device was able to reproduce similar process conditions/parameters (e.g., outlet temperature (Tout)) and to provide particles with similar drug–polymer miscibility and morphology as laboratory-scale SDSDs. These findings confirm that the design and operation of this novel screening equipment mimic the microscale evaporation mechanism of a larger spray-dryer. The miniaturized spray-dryer was therefore able to provide a rational prediction of adequate polymer and drug loading (DL) for SDSD development while reducing active pharmaceutical ingredient (API) consumption by a factor of 120 and cycle time by a factor of 4.
Development of a small-scale spray-drying approach for amorphous solid dispersions (ASDs) screening in early drug developmentThe present study details the development of a small-scale spray-drying approach for the routine screening of amorphous solid dispersions (ASDs). This strategy aims to overcome the limitations of standard screening methodologies like solvent casting and quench cooling to predict drug-polymer miscibility of spraydried solid dispersions (SDSDs) and therefore to guarantee appropriate carrier and drug-loading (DL) selection. A DoE approach was conducted to optimize process conditions of ProCept 4M8-TriX spray-drying to maximize the yield from a 100 mg batch of Itraconazole/HPMCAS-LF and Itraconazole/Soluplus 40:60 (w/w). Optimized process parameters include: inlet temperature, pump speed, drying and atomizing airflows. Identified process conditions derived from the DoE analysis were further i) tested with Itraconazole, Naproxen and seven polymers, ii) adapted for small cyclone use, iii) downscaled to 20 mg batch production. Drug-polymer miscibility was systematically characterized using modulated differential scanning calorimetry (mDSC). Spray-drying was identified as a well-suited screening approach: mean yield of 10.1 to 40.6% and 51.1 to 81.0% were obtained for 20 and 100 mg ASD productions, respectively.Additionally, this work demonstrates the interest to move beyond conventional screening approaches and integrate spray-drying during screening phases so that a greater prediction accuracy in terms of SDSDs miscibility and performance can be obtained.
Recently, glasses, a subset of amorphous solids, have gained attention in various fields, such as polymer chemistry, optical fibers, and pharmaceuticals. One of their characteristic features, the glass transition temperature (T g ) which is absent in 100% crystalline materials, influences several material properties, such as free volume, enthalpy, viscosity, thermodynamic transitions, molecular motions, physical stability, mechanical properties, etc. In addition to T g , there may be several other temperaturedependent transitions known as sub-T g transitions (or β-, γ-, and δ-relaxations) which are identified by specific analytical techniques. The study of T g and sub-T g transitions occurring in amorphous solids has gained much attention because of its importance in understanding molecular kinetics, and it requires the combination of conventional and novel characterization techniques. In the present study, three different analytical techniques [modulated differential scanning calorimetry (mDSC), dynamic mechanical analysis (DMA), and dielectric relaxation spectroscopy (DRS)] were used to perform comprehensive qualitative/quantitative characterization of molecular relaxations, miscibility, and molecular interactions present in an amorphous polymer (PVPVA), a model drug (indomethacin, IND), and IND/PVPVA-based amorphous solid dispersions (ASDs). This is the first ever reported DMA study on PVPVA in its powder form, which avoids the contribution of solvent to the mechanical properties when a selfstanding polymer film is used. A good correlation between the techniques in determining the T g value of PVPVA, IND, and IND/ PVPVA-based ASDs is established, and the negligible difference (within 10 °C) is attributed to the different material properties assessed in each technique. However, the overall T g behavior, the decrease in T g with increase in drug loading in ASDs, is universally observed in all the above-mentioned techniques, which reveals their complementarity. DMA and DRS techniques are used to study the different sub-T g transitions present in PVPVA, amorphous IND, and IND/PVPVA-based ASDs because these transitions are continued...
This work describes a novel screening strategy that implements small-scale spray-drying in early development of binary amorphous solid dispersions (ASDs). The proposed methodology consists of a three-stage decision protocol in which small batches (20–100 mg) of spray-dried solid dispersions (SDSDs) are evaluated in terms of drug–polymer miscibility, physical stability and dissolution performance in bio-predictive conditions. The objectives are to select the adequate carrier and drug-loading (DL) for the manufacturing of robust SDSD; and the appropriate stabilizer dissolved in the liquid vehicle of SDSD suspensions, which constitutes the common dosage form used during non-clinical studies. This methodology was verified with CDP146, a poorly water soluble (<2 µg/mL) API combined with four enteric polymers and four stabilizers. CDP146/HPMCAS-LF 40:60 (w/w) and 10% (w/v) PVPVA were identified as the lead SDSD and the best performing stabilizer, respectively. Lead SDSD suspensions (1–50 mg/mL) were found to preserve complete amorphous state during 8 h and maintain supersaturation in simulated rat intestinal fluids during the absorption window. Therefore, the implementation of spray-drying as a small-scale screening approach allowed maximizing screening effectiveness with respect to very limited API amounts (735 mg) and time resources (9 days), while removing transfer steps between screening and manufacturing phases.
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