A Novel Protocol Using Small-Scale Spray-Drying for the Efficient Screening of Solid Dispersions in Early Drug Development and Formulation, as a Straight Pathway from Screening to Manufacturing Stages

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

Prediction of Phase Behavior of Spray-Dried Amorphous Solid Dispersions: Assessment of Thermodynamic Models, Standard Screening Methods and a Novel Atomization Screening Device with Regard to Prediction Accuracy

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

Development of a small-scale spray-drying approach for amorphous solid dispersions (ASDs) screening in early drug development

The 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. Keywords: amorphous solid dispersions; spray-dryer; design of experiments; screening; miscibility; solvent casting; quench cooling; polymer

Screening Methods for the Development of Binary Spray-Dried Amorphous Solid Dispersions in Early Stage of Drug and Process Development

Amorphous solid dispersion (ASD) of a poorly soluble active pharmaceutical ingredient (API) in a polymeric matrix is a promising approach to increase the solubility, dissolution rate and hence bioavailability of the API. From an industrial point of view, spray-drying represents the main solvent evaporation process used for the manufacture of solid dispersions. The aim of the present PhD thesis was to evaluate the accuracy of: i) thermodynamic models (e.g. solubility parameter and Flory-Huggins theories), ii) standard screening methodologies (e.g. solvent casting and quench cooling) and iii) novel screening approaches for predicting the miscibility of binary spray-dried solid dispersions (SDSDs) so that the best performing API-polymer systems at adequate drug-loading (DL) can be selected. Two novel approaches for screening improvement, miniaturization and downscaling of regular spray-drying, were investigated and applied to API-polymer systems consisting of models drugs (Ibuprofen, Naproxen, Carbamazepine and Itraconazole) and seven polymers at four DLs. Screened samples were characterized using modulated differential scanning calorimetry (mDSC), X-ray powder diffraction (XRPD), thermo-gravimetric analysis (TGA) and scanning electron microscopy (SEM). Results obtained from miscibility and solid state characterization were compiled into principal components analysis (PCA) in order to qualitatively rank the screening approaches based upon their prediction accuracy. Non-sink dissolutions conditions with regard to the crystalline API were performed to assess the solubility enhancement and the extent of supersaturation of screened samples. The two proposed screening approaches were found to provide a greater accuracy than traditional screening methodologies to predict the miscibility of SDSDs. The limitations of theoretical models and standard screening methods tested are symptomatic of the gap existing between equilibrium solid solubility to kinetic miscibility as well as the importance of the preparation method with regard to ASD properties. Therefore, the main benefits of the novel approaches rely on their capacity to better reproduce the operating mode and process conditions of regular spray-dryer, while minimizing API needs for a production, significantly. The outcome of this work favours the downscaling approach due to its improved ability to ease the transfer from screening phases to manufacturing stage in the selection of adequate polymer and DL. In this regard, a novel three-stage decision protocol that implements spray-drying in a methodical small-scale approach for the development of ASDs during preclinical activities was developed and has successfully replaced all former practices in UCB projects

Comparison of a Novel Miniaturized Screening Device with Büchi B290 Mini Spray-Dryer for the Development of Spray-Dried Solid Dispersions (SDSDs)

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