Time and Temperature Dependence of Drug Crystallization─The Role of Molecular Mobility.

Using the time-temperature-transformation diagrams, we demonstrated a correlation between molecular mobility and crystallization in amorphous solid dispersions of nifedipine (NIF) with each polyvinylpyrrolidone vinyl acetate (PVPVA64) and polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus). The behavior was compared with the NIF dispersions prepared with each polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) [Lalge et al., Mol. Pharmaceutics 2023, 20(3), 1806-1817]. Each system was characterized by a unique temperature at which the crystallization onset time was the shortest. Below this temperature, a coupling was observed between the α-relaxation time determined by dielectric spectroscopy and crystallization onset time. Above this temperature, the activation barrier for crystallization had a more significant role than molecular mobility. In the solid state, PVP and PVPVA64 dispersion exhibited higher resistance to crystallization than HPMCAS and Soluplus. The role of polymers in inhibiting crystal growth in nucleated systems was discerned by monitoring crystallization following wetting of the amorphous dispersion with the dissolution medium. PVPVA64 and Soluplus dispersions exhibited higher resistance to crystal growth than PVP and HPMCAS.

Understanding the Effect of Nucleation in Amorphous Solid Dispersions through Time-Temperature Transformation.

In an earlier investigation, the critical cooling rate to prevent drug crystallization (CRcrit) during the preparation of nifedipine (NIF) amorphous solid dispersions (ASDs) was determined through a time-temperature transformation (TTT) diagram (Lalge et al. Mol. Pharmaceutics 2023, 20 (3), 1806-1817). The current study aims to use the TTT diagram to determine the critical cooling rate to prevent drug nucleation (CRcrit N) during the preparation of ASDs. ASDs were prepared with each polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). The dispersions were first stored under conditions promoting nucleation and then heated to the temperature that favors crystallization. The crystallization onset time (tC) was determined by differential scanning calorimetry and synchrotron X-ray diffractometry. TTT diagrams for nucleation were generated, which provided the critical nucleation temperature (50 °C) and the critical cooling rate to avoid nucleation (CRcrit N). The strength of the drug-polymer interactions as well as the polymer concentration affected the CRcrit N, with PVP having a stronger interaction than HPMCAS. The CRcrit of amorphous NIF was ∼17.5 °C/min. The addition of a 20% w/w polymer resulted in CRcrit of ∼0.05 and 0.2 °C/min and CRcrit N of ∼4.1 and 8.1 °C/min for the dispersions prepared with PVP and HPMCAS, respectively.

Implications of Drug-Polymer Interactions on Time-Temperature-Transformation: A Tool to Assess the Crystallization Propensity in Amorphous Solid Dispersions.

The critical cooling rate (CRcrit) to prevent drug crystallization during the preparation of nifedipine amorphous solid dispersions (ASDs) was determined through the time-temperature-transformation (TTT) diagram. ASDs were prepared with polyvinylpyrrolidone, hydroxypropylmethyl cellulose acetate succinate, and poly(acrylic acid). ASDs were subjected to isothermal crystallization over a wide temperature range, and the time and temperature dependence of nifedipine crystallization onset time (tC) was determined by differential scanning calorimetry (DSC) and synchrotron X-ray diffractometry. TTT diagrams were generated for ASDs, which provided the CRcrit for the dispersions prepared with each polymer. The observed differences in CRcrit could be explained in terms of differences in the strength of interactions. Stronger drug-polymer interactions led to longer tC and decreased CRcrit. The effect of polymer concentrations (4-20% w/w) was also influenced by the strength of the interaction. The CRcrit of amorphous NIF was ∼17.5 °C/min. Addition of 20% w/w polymer resulted in a CRcrit of ∼0.05, 0.2, and 11 °C/min for the dispersions prepared with PVP, HPMCAS, and PAA, respectively.

Design of Ternary Amorphous Solid Dispersions for Enhanced Dissolution of Drug Combinations.

Using sulfamethoxazole (SMZ) and trimethoprim (TMP) as model drugs, we designed amorphous solid dispersions (ASDs) for the simultaneous solubility enhancement of two active pharmaceutical ingredients (APIs) by exploiting the drug-drug and drug-polymer interactions. In order to make this approach broadly applicable and over a wide dose range, a mixture of SMZ and TMP at weight ratios of 5:1 and 1:5 (w/w) were formulated into ternary ASDs. Depending on the dose ratio of the two drugs, the polymer used was either an aminoalkyl methacrylate copolymer (Eudragit, EDE) or polyacrylic acid. The drug-drug and drug-polymer interactions were characterized to be ionic by infrared and solid-state nuclear magnetic resonance spectroscopy. The interactions resulted in a substantial reduction in molecular mobility, evident from the increase in the structural relaxation time determined by dielectric spectroscopy. The drug-drug interaction resulted in ∼3 orders of magnitude reduction in molecular mobility. The addition of a polymer led to a further decrease in molecular mobility of up to 4 orders of magnitude. The strength of intermolecular interactions was also estimated from the glass transition temperatures of the ASDs obtained by differential scanning calorimetry. The strong intermolecular interactions yielded highly stable ASDs with no evidence of crystallization, both at elevated temperatures and under accelerated storage conditions (40 °C/75% relative humidity; 6 weeks). The dissolution performances of the ASDs were evaluated using the area under the curve (AUC) obtained from the concentration-time profiles under the non-sink condition. SMZ and TMP in their ternary ASDs, when compared with their crystalline counterparts, exhibited up to 6.4- and 4.6-fold increases in AUC, respectively. Importantly, the synchronized release of the two drugs was observed, a desirable attribute in synergistic formulations. A single-phase ternary ASD, stabilized by drug-drug and drug-polymer interactions, is likely responsible for the unique release profile.

Nanobubbles in Reconstituted Lyophilized Formulations: Interaction With Proteins and Mechanism of Formation.

Reconstitution of lyophilized disaccharide formulations results in the formation of nanosized air bubbles that persist in suspension for weeks. If proteins are present, interactions with nanobubbles may cause loss of monomeric protein and formation of subvisible particles. The goals of this work are to determine the mechanism(s) by which nanobubbles form in reconstituted lyophilized formulations and to develop strategies for reducing nanobubble generation. We hypothesize that nanobubbles are created from nanosized gas pockets within lyophilized solids, which become bubbles when the surrounding matrix is dissolved away during reconstitution. Nanosized voids may originate from small ice crystals formed within the concentrated liquid during freezing that subsequently sublime during drying. Nanobubble concentrations are correlated with the extent of mannitol crystallization during freezing. Nanosized ice crystals, induced by the release of water during mannitol crystallization, were responsible for nanobubble formation. The presence of trehalose or sucrose, in formulations with low mannitol concentrations, inhibited excipient crystallization during lyophilization and reduced nanobubble levels following reconstitution. Our results show a correlation between nanobubble formation and concentrations of insoluble IL-1ra aggregates, suggesting that minimizing nanobubble generation may be an effective strategy for reducing protein aggregation following reconstitution.

Crosslinking: An avenue to develop stable amorphous solid dispersion with high drug loading and tailored physical stability.

Influence of crosslinking (crosslinker concentration and crosslinking condition) on molecular mobility and physical stability of ketoconazole (KTZ) solid dispersions was investigated over a wide temperature range in the supercooled state. Amorphous solid dispersions (ASDs) with very high drug loading (95% w/w) were prepared by thermal crosslinking. As the crosslinker concentration increased (from 0.25-1.0% w/w), there was a progressive decrease in molecular mobility as evident from both the longer α-relaxation time, and higher viscosity values. Consequently, there was progressive enhancement in physical stability (crystallization inhibition). At 1.0% w/w crosslinker concentration, when compared with the drug alone, there was ~4 orders of magnitude increase in both viscosity and α-relaxation times. Elevating the crosslinking temperature, by increasing the crosslinking density, provided a second avenue to enhance physical stability. Hence, crosslinking density offers a simple method to enhance physical stability and control drug release. We have formulated ASDs: (i) with very high drug loading (95% w/w), and (ii) pronounced stability even when exposed to elevated temperatures and water vapor pressure. Also, during dissolution study, the degree of supersaturation in the dissolution medium generated by the crosslinked systems gradually increased and maintained the supersaturation for a longer period.

A supramolecular synthon approach to design amorphous solid dispersions with exceptional physical stability.

A supramolecular synthon approach was exploited to design amorphous solid dispersions (ASDs) of drugs containing an amino aromatic nitrogen moiety and a polyacrylic acid polymer. The interaction between a drug and polymer was confirmed by differential scanning calorimetry, spectroscopy (IR and 15N NMR), and X-ray crystallography. The interaction decreased the molecular mobility, conferred exceptional physical stability and enhanced the drug dissolution.

Molecular dynamics of amorphous pharmaceutical fenofibrate studied by broadband dielectric spectroscopy.

Fenofibrate is mainly used to reduce cholesterol level in patients at risk of cardiovascular disease. Thermal transition study with the help of differential scanning calorimetry (DSC) shows that the aforesaid active pharmaceutical ingredient (API) is a good glass former. Based on our DSC study, the molecular dynamics of this API has been carried out by broadband dielectric spectroscopy (BDS) covering wide temperature and frequency ranges. Dielectric measurements of amorphous fenofibrate were performed after its vitrification by fast cooling from a few degrees above the melting point (Tm=354.11 K) to deep glassy state. The sample does not show any crystallization tendency during cooling and reaches the glassy state. The temperature dependence of the structural relaxation has been fitted by single Vogel-Fulcher-Tamman (VFT) equation. From VFT fit, glass transition temperature (Tg) was estimated as 250.56 K and fragility (m) was determined as 94.02. This drug is classified as a fragile glass former. Deviations of experimental data from Kohlrausch-Williams-Watts (KWW) fits on high-frequency flank of α-peak indicate the presence of an excess wing in fenofibrate. Based on Ngai׳s coupling model, we identified the excess wing as true Johari-Goldstein (JG) process. Below the glass transition temperature one can clearly see a secondary relaxation (γ) with an activation energy of 32.67 kJ/mol.