Crystallization Tendency of Pharmaceutical Glasses: Relevance to Compound Properties, Impact of Formulation Process, and Implications for Design of Amorphous Solid Dispersions

Abstract

Amorphous solid dispersions (ASDs) are important formulation strategies for improving the dissolution process and oral bioavailability of poorly soluble drugs. Physical stability of a candidate drug must be clearly understood to design ASDs with superior properties. The crystallization tendency of small organics is frequently estimated by applying rapid cooling or a cooling/reheating cycle to their melt using differential scanning calorimetry. The crystallization tendency determined in this way does not directly correlate with the physical stability during isothermal storage, which is of great interest to pharmaceutical researchers. Nevertheless, it provides important insights into strategy for the formulation design and the crystallization mechanism of the drug molecules. The initiation time for isothermal crystallization can be explained using the ratio of the glass transition and storage temperatures (Tg/T). Although some formulation processes such as milling and compaction can enhance nucleation, the Tg/T ratio still works for roughly predicting the crystallization behavior. Thus, design of accelerated physical stability test may be possible for ASDs. The crystallization tendency during the formulation process and the supersaturation ability of ASDs may also be related to the crystallization tendency determined by thermal analysis. In this review, the assessment of the crystallization tendency of pharmaceutical glasses and its relevance to developmental studies of ASDs are discussed.

Thermal Stability of Amorphous Solid Dispersions

“…Hot melt extrusion (HME) and spray drying (SD) are among the most employable methods for ASD design. Recent advances in HME and SD expedited commercial and industrial application of amorphous solid dispersion concepts for poorly soluble drugs [ 67 , 70 , 103 , 104 ]. Examples of commercially available drugs include HME (lumacaftor/HPMCAS/SLS, posaconazole/HPMCAS, griseofluvin/PEG, ritonavir/PVP/PA, lopinavir/PVP/VA), and SD (telaprevir/HPMCAS, etravirine/HPMC, itroconazol/HPMC, tacrolimus/HPMC, rosuvastatin/HPMC) [ 105 , 106 ].…”

Opportunities for Successful Stabilization of Poor Glass-Forming Drugs: A Stability-Based Comparison of Mesoporous Silica Versus Hot Melt Extrusion Technologies

“…There are only a handful of known GFA-I compounds that are also BCS II compounds and which would thus benefit from the apparent solubility increase of the amorphous form. In a recent review, Kawakami provided an overview of pharmaceutical compounds according to GFA classes [45]. Of the GFA-I compounds in the database only 29% were determined to be BCS II/IV, which is far lower than the commonly reported percentage of commercial compounds that fall into the poor solubility category (60%) [8].…”

“…However, it was observed that dissolution of API loaded silica formulations remained consistent throughout the 3 month study (Figure 8; Figure 9), whereas the kinetic release of HME formulations tended towards crystalline drug solubility (Figure 8; Figure 9). Here, we see the effect of phase separation and recrystallization on the dissolution performance of amorphous solid dispersions, with the presence of a crystalline phase reducing the achievable supersaturation and decreasing the dissolution performance of the compound [45]. Interestingly, both HME formulations retained some supersaturation after the first month of the stability study, indicating that full conversion from amorphous to crystalline had not yet occurred (Figure 8; Figure 9).…”

Bioavailability Improvement of Carbamazepine via Oral Administration of Modified-Release Amorphous Solid Dispersions in Rats

“…After 120 min, 250 mL 0.2 M Na 3 PO 4 solution (equilibrated to 37 ± 0.5 • C) was added to vessel to adjust the pH of the medium to 6.8. During testing, samples (0.6 mL for each) were withdrawn from vessel at predefined intervals (2,5,10,20,30,45,60,120,125,130,140,150,180,240,360, and 480 min) and immediately filtered with 0.45 µm filter. A 0.3 mL filtrate was diluted with 0.3 mL methanol for HPLC analysis, as in Section 2.4.6.…”

“…This poor water solubility results in additional problems. A low drug dissolution rate will limit drug bioavailability after oral administration, especially for biopharmaceutical classification system class II (BCS II) drugs, which have poor water solubility and high permeability [4,5]. Therefore, enhancement of the dissolution rate plays a crucial role in improving the oral bioavailability of BCS II drugs.…”