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., 2023, (3), 1806-1817].

Excipient-Induced Lattice Disorder in Active Pharmaceutical Ingredient: Implications on Drug Product Continuous Manufacturing.

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.

Effect of surfactants on lactate dehydrogenase aqueous solutions: A comparative study of poloxamer 188, polysorbate 20 and 80.

The effect of three commonly used surfactants, poloxamer 188 (P188), polysorbate 20 and 80 (PS20 and PS80), on the stability of a model protein, lactate dehydrogenase (LDH), was compared in aqueous solutions. In the absence of a surfactant, protein solution revealed a gradual decrease in surface tension as a function of time. The addition of surfactant resulted in a rapid decrease in the surface tension.

Probing Chemical Equilibrium in Frozen Sodium Phosphate Buffer Solution by P Solid-State NMR.

Phosphate buffers are crucial for cryopreservative stability in pharmaceuticals, food processing, biomedical sciences, and biology. However, their freeze concentrates lack quantitative characterization, especially regarding the physicochemical properties of phosphate salt species in equilibrium at subzero temperatures. This study employs P solid-state NMR (ssNMR) to analyze frozen sodium phosphate (NaP) solutions, providing insights into phase composition, ionic strength, and pH.

Dual Functionality of Poloxamer 188 in Freeze-Dried Protein Formulations: A Stabilizer in Frozen Solutions and a Bulking Agent in Lyophiles.

Poloxamer 188 (P188) was hypothesized to be a dual functional excipient, (i) a stabilizer in frozen solution to prevent ice-surface-induced protein destabilization and (ii) a bulking agent to provide elegant lyophiles. Based on X-ray diffractometry and differential scanning calorimetry, sucrose, in a concentration-dependent manner, inhibited P188 crystallization during freeze-drying, while trehalose had no such effect. The recovery of lactate dehydrogenase (LDH), the model protein, was evaluated after reconstitution.

Impact of Excipient Extraction and Buffer Exchange on Recombinant Monoclonal Antibody Stability.

The foundation of a biosimilar manufacturer's regulatory filing is the demonstration of analytical and functional similarity between the biosimilar product and the pertinent originator product. The excipients in the formulation may interfere with characterization using typical analytical and functional techniques during this biosimilarity exercise. Consequently, the producers of biosimilar products resort to buffer exchange to isolate the biotherapeutic protein from the drug product formulation.

Solid-State NMR Spectroscopy to Probe State and Phase Transitions in Frozen Solutions.

Freezing is commonly encountered during the processing and storage of biomacromolecule products. Therefore, understanding the phase and state transitions in pharmaceutical frozen solutions is crucial for the rational development of biopharmaceuticals. Solid-state nuclear magnetic resonance spectroscopy (ssNMR) was used to analyze solutions containing sodium phosphate buffer, histidine, and trehalose.

Role of Poloxamer 188 in Preventing Ice-Surface-Induced Protein Destabilization during Freeze-Thawing.

The phase behavior of poloxamer 188 (P188) in aqueous solutions, characterized by differential scanning calorimetry (DSC) and synchrotron X-ray diffractometry, revealed solute crystallization during both freezing and thawing. Sucrose and trehalose inhibited P188 crystallization during freeze-thawing (FT). While trehalose inhibited P188 crystallization only during cooling, sucrose completely suppressed P188 crystallization during both cooling and heating.

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 (CR) 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).

Drug Phase Transformation and Water Redistribution during Continuous Tablet Manufacturing: A Case Study of Carbamazepine Dihydrate.

In recent years, continuous tablet manufacturing technology has been used to obtain regulatory approval of several new drug products. While a significant fraction of active pharmaceutical ingredients exists as hydrates (wherein water is incorporated stoichiometrically in the crystal lattice), the impact of processing conditions and formulation composition on the dehydration behavior of hydrates during continuous manufacturing has not been investigated. Using powder X-ray diffractometry, we monitored the dehydration kinetics of carbamazepine dihydrate in formulations containing dibasic calcium phosphate, anhydrous (DCPA), mannitol, or microcrystalline cellulose.

Enabling Efficient Design of Biological Formulations Through Advanced Characterization.

The present review summarizes the use of differential scanning calorimetry (DSC) and scattering techniques in the context of protein formulation design and characterization. The scattering techniques include wide angle X-ray diffractometry (XRD), small-angle neutron scattering (SANS) and small-angle X-ray scattering (SAXS). While DSC is valuable for understanding thermal behavior of the excipients, XRD provides critical information about physical state of solutes during freezing, annealing and in the final lyophile.

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

The critical cooling rate (CR) 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 () was determined by differential scanning calorimetry (DSC) and synchrotron X-ray diffractometry.

Mannitol as an Excipient for Lyophilized Injectable Formulations.

The review summarizes the current state of knowledge of mannitol as an excipient in lyophilized injectable small and large molecule formulations. When compared with glycine, the physicochemical properties of mannitol make it a desirable and preferred bulking agent. Though mannitol is a popular bulking agent in freeze-dried formulations, its use may pose certain challenges such as vial breakage or its existence as a metastable crystalline hemihydrate in the final cake, necessitating appropriate mitigation strategies.

Frozen storage of proteins: Use of mannitol to generate a homogenous freeze-concentrate.

Therapeutic proteins may be subjected to several freeze-thaw cycles throughout manufacturing and storage. The protein solution composition and the freezing conditions may lead to incomplete ice crystallization in the frozen state. This can also result in freeze-concentrate heterogeneity characterized by multiple glass transition temperatures and protein destabilization.

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.

Mannitol hemihydrate in lyophilized protein formulations:Impact of its dehydration during storage on sucrose crystallinity and protein stability.

The high propensity of mannitol to crystallize in frozen solutions along with its high eutectic temperature enabling higher primary drying temperatures makes it a good bulking agent. In protein formulations, addition of a sugar (sucrose) that has the ability to remain amorphous throughout processing as well as storage is imperative to retain the protein in its native state. It is well known that in the presence of amorphous excipients and protein, mannitol can crystallize as a mixture of anhydrous polymorphs - α-, β- and δ-forms and a hemihydrate form [mannitol hemihydrate (MHH); CHO·0.

Dual Functionality of Bile Acid: Physical Stabilization of Drugs in the Amorphous Form and Solubility Enhancement in Solution.

Drugs containing an amino aromatic nitrogen moiety were stabilized in the amorphous form by the surfactant cholic acid (CA). Coamorphous systems of lamotrigine (LAM), pyrimethamine (PYR), and trimethoprim (TRI) were each prepared with CA. Drug-CA interactions, investigated by IR and solid-sate NMR spectroscopy, revealed deprotonation of the carboxylic acid group in CA and the protonation of the most basic nitrogen of the drug.

Succinate Buffer in Biologics Products: Real-world Formulation Considerations, Processing Risks and Mitigation Strategies.

The succinic acid/succinate system has an excellent buffering capacity at acidic pH values (4.5-6.0), promising to be a buffer of choice for biologics having slightly acidic to basic isoelectric points (pI 6 - 9).

Role of arginine salts in preventing freezing-induced increase in subvisible particles in protein formulations.

While arginine hydrochloride (ArgHCl) has emerged as a potential stabilizer of protein drugs in liquid formulations, the purpose of this manuscript was to evaluate its stabilization potential in frozen solutions. The phase behavior of frozen ArgHCl solutions was investigated by differential scanning calorimetry and low temperature powder X-ray diffractometry. The aggregation of β-galactosidase was evaluated following freeze-thaw cycling in ArgHCl solutions with and without mannitol.

Crystallization Propensity of Amorphous Pharmaceuticals: Kinetics and Thermodynamics.

Four model compounds, nifedipine, indomethacin, felodipine, and ketoconazole, all with nearly identical glass transition temperatures, were chosen to study the effects of thermodynamics and molecular mobility on their crystallization propensities. The time and temperature dependence of the crystallization induction time of each compound was determined by differential scanning calorimetry (DSC) and enabled the generation of their time-temperature-transformation (TTT) diagrams. The relaxation times (τ) were measured by dielectric spectroscopy, and the Gibbs free energy (Δ) and entropy (Δ) difference between the crystalline and amorphous states were obtained by DSC.

Reversible Self-Association in Lactate Dehydrogenase during Freeze-Thaw in Buffered Solutions Using Neutron Scattering.

The aims of this work were to evaluate the effect of freezing and thawing stresses on lactate dehydrogenase (LDH) stability under three conditions. (i) In a solution buffered with sodium phosphate (NaP; 10 and 100 mM). The selective crystallization of disodium hydrogen phosphate during freezing caused a pronounced pH shift.

Use of Atomic Force Microscopy (AFM) to monitor surface crystallization in caffeine-oxalic acid (CAFOXA) cocrystal compacts.

Our objective was to monitor the surface crystallization in disordered caffeine-oxalic acid (CAFOXA) cocrystals following exposure to elevated water vapor pressure. This was accomplished using atomic force microscopy (AFM). Disorder was induced in the cocrystal particles by the common pharmaceutical unit operations of milling and compaction.

Phase behavior of poloxamer 188 in frozen aqueous solutions - Influence of processing conditions and cosolutes.

The aim of the study is to investigate the thermal behavior of poloxamer 188 (P188) in binary (P188-water) and ternary (P188-trehalose-water) solutions during freezing and thawing. The thermal behavior of P188 in frozen (binary and ternary) systems was characterized by differential scanning calorimetry (DSC) and low-temperature X-ray powder diffractometry (XPRD) as a complementary technique. The influence of processing conditions (cooling rate, annealing) and a noncrystallizing co-solute (addition of trehalose) on the behavior of P188 was evaluated during freezing as well as thawing.

Levothyroxine Sodium Pentahydrate Tablets - Formulation Considerations.

Even though levothyroxine sodium pentahydrate tablets have been in the market since 1955, there continue to be recalls due to sub potency. We have comprehensively reviewed the factors affecting its stability in solid oral dosage forms. A compilation of marketed formulation compositions enabled the identification of the potential 'problem excipients'.

Investigating the Influence of Excipients on the Stability of Levothyroxine Sodium Pentahydrate.

A range of tablet excipients were evaluated for their influence on the physical form and chemical stability of levothyroxine sodium pentahydrate (LSP; CHINNaO·5HO). LSP-excipient binary powder blends were stored under two conditions: (a) in hermetically sealed containers at 40 °C and (b) at 40 °C/75% RH. By use of synchrotron X-ray diffractometry, the disappearance of LSP could be quantified and the appearance of crystalline levothyroxine (free acid) could be identified.