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 (T_g/T). Although some formulation processes such as milling and compaction can enhance nucleation, the T_g/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.

Keywords: accelerated stability test; crystallization; crystallization tendency; milling; nucleation; pharmaceutical glass.

Figure 1

Schematic representation of hot (non-isothermal) and isothermal crystallization.

Figure 2

Examples of cooling/reheating differential scanning calorimetry (DSC) curves from the melt: (a) cooling curves of haloperidol (Class 1) at various cooling rates, as indicated in the figure; (b) cooling/reheating curves of acetaminophen (Class 2); and (c) cooling/reheating curves of fenofibrate (Class 3).

Figure 3

Visualization of: (a) molecular weight; and (b) melting enthalpy of compounds belonging to each class.

Figure 4

Schematic representation of the temperature dependence of the nucleation and crystal growth temperatures for Classes 1 and 2 compounds.

Figure 5

Reheating DSC curves of celecoxib melt, illustrating the dependence of the cold crystallization on the target temperature of the cooling process (shown in the figure).

Figure 6

Initiation time of crystallization (t₁₀, min) as a function of T_g/T. The q and FD labels in the parentheses indicate that the glass was prepared by quenching and freeze-drying, respectively. The numbers in parentheses denote the crystallization tendency classification. The universal line is the best fit for Classes 1 and 2 compounds (ln(t₁₀) = 66.2T_g/T − 57.0).

Figure 7

Isothermal crystallization of indomethacin glasses at 30 °C under dried condition. (■) Quenched and ground for 6 min. Crystallized to form γ [51]. (◇) Quenched and ground. Crystallized to form α except that symbols with asterisk involves small amount of form γ [54]. (●) Quenched and cryoground. Crystallized to mixture of form α and γ (our data). (▲) Quenched. Crystallized to form γ [55]. (○) Quenched and stored in DSC pan (our data). Crystallized to form α which contains small amount of form γ.

Figure 8

Onset crystallization time (t_o, min) of nifedipine glass as a function of T_g/T. (■) After the pretreatment (see text), quenched in hermetically sealed pan (our data) [44]. (○) Quenched in sealed DSC pan without pretreatment (our data). (●) Quenched in DSC pan [57]. (▲) Quenched on glass slides and crystallization was observed by polarized light microscopy [56]. Cracked glasses were excluded from the analysis. (◆) Quenched in DSC pan [58]. All the literature data were recalculated using the T_g value of 45.5 °C. Definition of onset crystallization time, which is analogous to t₁₀, is slightly different depending on literature, but its impact is ignorable in the analysis here.

Figure 9

Effect of compression pressure on crystallization heat flow curves of sucrose glasses investigated by isothermal microcalorimetry (30 °C). Freeze-dried sucrose was compressed at pressure of ca. 2.5 MPa (black), 0.5 MPa (red), or 0.1 MPa (blue) for 10 s and subjected to the measurement.

Figure 10

Onset crystallization time (t_o, min) of various ASDs as a function of T_g/T. (◆,◆,◇) Nifedipine/PVP ASDs prepared by melt–quench [68,69] followed by milling [58], respectively. (●, ●) Phenobarbital/PVP ASDs prepared by melt–quench [68,69]. (▲,△) Sanofi–Aventis compound/HPMCP ASDs prepared by spray-drying stored under dried and humid conditions, respectively [70]. Definition of onset crystallization time, which is analogous to t₁₀, is slightly different depending on the study, but its impact is ignorable in the analysis here. HPMCP, Hydroxypropyl methylcellulose phthalate.