Raj Suryanarayanan

The Tnose for nucleation (i.e., the temperature of the maximum nucleation rate without any crystal growth) of flurbiprofen-polyvinylpyrrolidone amorphous solid dispersions (ASDs) was determined using the time−temperature−transformation (TTT) diagram. Varying levels of nucleation were induced in ASDs by annealing for different time periods at Tnose for nucleation. Synchrotron X-ray diffractometry was utilized for real-time monitoring of the crystallization behavior upon wetting the ASDs with water. An increase in the nucleation density shortened the lag time and also accelerated drug crystallization. Williamson−Hall analysis of the X-ray data revealed a progressive reduction in the lattice strain (increased lattice order) of the crystallizing phase with increasing contact time with water. From performance perspectives, actualizing the solubility advantage of the amorphous drug necessitates retaining supersaturation for a sufficiently long period to allow absorption from the gastrointestinal tract. However, the presence of nuclei, by facilitating crystallization, can negate the solubility and the consequent bioavailability advantage of ASDs. A systematic framework for evaluating the “health” of ASDs was established, highlighting that the absence of nuclei would be an essential attribute of robust ASDs.

In high-drug-loaded amorphous solid dispersions, effective stabilization requires polymers that can hinder nucleation as well as crystal growth. We hypothesized that combining two polymers with complementary stabilization mechanisms would enhance physical stability more effectively than the individual polymers. Evaluation of single-polymer systems at a polymer loading of 20% w/w showed that HPMCAS (hydroxypropyl methylcellulose acetate succinate) had the highest thermodynamic miscibility with carbamazepine (CBZ), whereas PVP (polyvinylpyrrolidone) and PVPVA (PVP/vinyl acetate) dispersions had the longest α-relaxation time. Based on these findings, ternary systems combining 80% w/w CBZ, 10% w/w HPMCAS, and 10% w/w of either PVP or PVPVA were evaluated. The ternary systems exhibited longer crystallization onset times than the corresponding single-polymer systems at the same total polymer loading. The improved stability was due to a synergistic mechanism where HPMCAS provided resistance to nucleation by increasing the activation energy barrier, while PVP/PVPVA kinetically lowered the attempt jump frequency to suppress both nucleation and crystal growth. This dual-polymer approach provided a basis for designing amorphous solid dispersions with high drug loading and improved physical stability.

Residual water in freeze-dried protein formulations plays a critical role in molecular relaxation behavior. In a previous study (Kumar et al., Mol Pharmaceutics 2025, 22, 4125–4136), we examined the impact of sucrose concentration on native structure retention in monoclonal antibody (mAb)–sucrose systems. The present work investigates how residual water content affects relaxation dynamics in this formulation system. Water affinity was first assessed via sorption isotherms across a range of water activities. There was an increase in residual water content as a function of mAb content in freeze-dried formulations. mAb–sucrose interactions were evident from detailed analyses of sorption data. There was a progressive decrease in the glass transition temperature with increasing water content. Dielectric spectroscopy was then employed to characterize the β- and γ-relaxation processes in the glassy state. While the β-relaxation time decreased with increasing water content, there was no significant effect on the corresponding activation energy. The effect of water content on the γ-relaxation was complex, with an increase in activation energies as a function of water content. In light of the influence of mobility on both physical and chemical stability, these results underscore the importance of controlling water content in optimizing the stability of freeze-dried mAb formulations.

Polymers play a pivotal role in amorphous solid dispersion (ASD) formulations. An ideal polymer must possess several attributes: it must maintain solid-state stability (retention of drug in the amorphous state), sustain the drug in a supersaturated state in the GI fluids (following administration), and have no detrimental effect on the drug permeation potential. In this study, indomethacin (IMC) ASDs were prepared with each hydroxypropyl methylcellulose acetate succinate (HPMCAS), poly(vinylpyrrolidone vinyl acetate) (PVPVA), or amino methacrylate copolymer (Eudragit E PO, EPO) were evaluated for their solid-state stability, dissolution behavior, and in vitro drug permeation using the parallel artificial membrane permeability assay (PAMPA). Solid-state stability was investigated through Flory-Huggins interaction parameters, and the molecular mobility was quantified using dielectric spectroscopy. Additionally, water-solid interactions and stability under accelerated conditions provided an assessment of the impact of drug-polymer interactions. Stability was rank ordered: IMC-EPO > IMC-PVPVA > IMC-HPMCAS, with IMC-EPO demonstrating superior resistance to crystallization. With respect to achieving supersaturation, the rankings were: IMC-HPMCAS > IMC-PVPVA > Amorphous IMC > IMC-EPO. While PVPVA and HPMCAS helped achieved the highest supersaturation, EPO was comparable to the amorphous drug. The rank ordering with respect to drug flux was: IMC-PVPVA > IMC-HPMCAS > Amorphous IMC ≈ IMC-EPO > Crystalline IMC. Thus, IMC-PVPVA offered a favorable compromise between physical robustness and permeation efficiency. These findings highlight the importance of polymer selection in ASD design─not only for maintaining physical stability, but also for ensuring effective drug dissolution and permeation.

Sucrose is the most common stabilizer used in freeze-dried protein formulations. We have investigated, using several methods, the effect of monoclonal antibody (mAb) to sucrose weight ratio on the thermal, relaxation, and water sorption behavior of freeze-dried formulations. The influence of the sucrose content on the miscibility and retention of the native structure of mAb was also investigated. With decreasing mAb-to-sucrose weight ratio, the following effects were observed. Differential scanning calorimetry revealed a progressive decrease in the glass transition temperature of the formulation, while, based on dielectric spectroscopy, the α-relaxation time decreased, whereas both the β- and γ-relaxation times increased. The ¹H T₁ relaxation time of the antibody, determined by solid-state nuclear magnetic resonance spectroscopy, followed the same trend as the β-relaxation time. Finally, infrared spectroscopy indicated that the optimal retention of the native-like secondary structure of the antibody was achieved at a 4:1 mAb-to-sucrose weight ratio. At mAb-to-sucrose weight ratios of 1:1 and lower, there was no evidence of phase separation in the 20-50 nm scale. Taken together, the results provide new insights into the solid-state behavior of the antibody-sucrose system.

Mannitol is widely employed as a bulking agent in lyophilized formulations. Our goal was to evaluate the role of noncrystallizing cosolutes in inhibiting mannitol crystallization and preventing the formation of mannitol hemihydrate (MHH) in frozen solutions. The individual influence of two common stabilizers (sucrose and trehalose) and three model proteins (lysozyme, bovine serum albumin, and immunoglobulin G) on the crystallization behavior of mannitol was investigated by differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). Sugars exerted a more pronounced crystallization inhibitory effect than proteins. In the presence of sugars, mannitol predominantly crystallized as MHH while the proteins facilitated the crystallization of δ-mannitol. Annealing the frozen solutions at -25 °C favored MHH crystallization. A higher annealing temperature of -10 °C accelerated mannitol crystallization and promoted the formation of the anhydrous δ-polymorph. The crystallization inhibitory effect of proteins was surmounted with annealing, while at a high sugar concentration, a substantial fraction of mannitol was retained amorphous even after annealing.

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.

Our previous work (Mol Pharm, 20 (2023) 3427) showed that crystalline excipients, specifically anhydrous dibasic calcium phosphate (DCPA), facilitated the dehydration of carbamazepine dihydrate (CBZDH) and the formation of an amorphous product phase during the mixing stage of continuous tablet manufacturing. Understanding the mechanism of this excipient-induced effect was the object of this study. Blending with DCPA for 15 min caused pronounced lattice disorder in CBZDH. This was evident from the 190% increase in the apparent lattice strain determined by the Williamson-Hall plot. The rapid dehydration was attributed to the increased reactivity of CBZDH caused by this lattice disorder. Lattice disorder in CBZDH was induced by a second method, cryomilling it with DCPA. The dehydration was accelerated in the milled sample. Annealing the cryomilled sample reversed the effect, thus confirming the effect of lattice disorder on the dehydration kinetics. The hardness of DCPA appeared to be responsible for the disordering effect. DCPA exhibited a similar effect in other hydrates, thereby revealing that the effect was not unique to CBZDH. However, its magnitude varied on a case-by-case basis. The high shear powder mixing was necessary for rapid and efficient powder mixing during continuous drug product manufacturing. The mechanical stress imposed on the CBZDH, and exacerbated by DCPA, caused this unexpected destabilization.