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. While low LDH recovery (∼60%) was observed in the lyophiles prepared with P188, the addition of sugar improved the activity recovery to >85%. The secondary structure of LDH in the freeze-dried samples was assessed using infrared spectroscopy, and only moderate structural changes were observed in the lyophiles formulated with P188 and sugar. Thus, P188 can be a promising dual functional excipient in freeze-dried protein formulations. However, P188 alone does not function as a lyoprotectant and needs to be used in combination with a sugar.

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. However, the impact that this isolation has on the product stability is not completely known. This study aims to elucidate the extent to which mAb isolation via ultrafiltration-diafiltration-based buffer exchange impacts mAb stability. It has been demonstrated that repeated extraction cycles do result in significant changes in higher-order structure (red-shift of 5.0 nm in fluorescence maxima of buffer exchanged samples) of the mAb and also an increase in formation of basic variants from 19.1 to 26.7% and from 32.3 to 36.9% in extracted innovator and biosimilar Tmab samples, respectively. It was also observed that under certain conditions of tertiary structure disruptions, Tmab could be restabilized depending on formulation composition. Thus, mAb isolation through extraction with buffer exchange impacts the product stability. Based on the observations reported in this paper, we recommend that biosimilar manufacturers take into consideration these effects of excipients on protein stability when performing biosimilarity assessments.

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. Lactate dehydrogenase (LDH) served as a model protein to evaluate the stabilizing effect of P188. The ability of P188, over a concentration range of 0.003-0.800% w/v, to prevent LDH (10 µg/mL) destabilization was evaluated. After five FT cycles, the aggregation behavior (by dynamic light scattering) and activity recovery were evaluated. While LDH alone was sensitive to interfacial stress, P188 at concentrations of ≥0.100% w/v stabilized the protein. However, as the surfactant concentration decreased, protein aggregation after FT increased. The addition of sugar (1.0% w/v; sucrose or trehalose) improved the stabilizing function of P188 at lower concentrations (≤0.010% w/v), possibly due to the inhibition of surfactant crystallization. Based on a comparison with the stabilization effect of polysorbate (both 20 and 80), it was evident that P188 could be a promising alternative surfactant in frozen protein formulations. However, when the surfactant concentration is low, the potential for P188 crystallization and the consequent compromise in its functionality warrant careful consideration.

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.

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.

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. The combined effect of nitrogen flow and vigorous mixing during the continuous mixing stage of tablet manufacture facilitated API dehydration. Dehydration was rapid and most pronounced in the presence of DCPA. The dehydration product, amorphous anhydrous carbamazepine, sorbed a significant fraction of the water released by dehydration. Thus, the dehydration process resulted in a redistribution of water in the powder blend. The unintended formation of an amorphous dehydrated phase, which tends to be much more reactive than its crystalline counterparts, is of concern and warrants further investigation.

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. Upon freezing, crystallization of disodium phosphate hydrogen dodecahydrate (Na2HPO4·12H2O, DPDH) and histidine was identified using 31P and 13C ssNMR, respectively, and confirmed by synchrotron X-ray diffractometry (SXRD). Using histidine as a molecular probe and based on the chemical shifts of atoms of interest, the pH of the freeze concentrate was measured. The unfrozen water content in freeze concentrates was quantified by 1H single pulse experiments. 13C-insensitive nuclei enhancement by polarization transfer (INEPT) and cross-polarization (CP) experiments were used as orthogonal tools to characterize the solutes in a "mobile" and a more "solid-like" state in the freeze-concentrated solutions, respectively. The above analyses were applied to a commercial monoclonal antibody (mAb) formulation of dupilumab. This work further establishes ssNMR spectroscopy as a highly capable biophysical tool to investigate the attributes of biopharmaceuticals and thereby provide insights into process optimization and formulation development.

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. However, as these techniques lack the sensitivity to detect biomolecule-related transitions, complementary characterization techniques such as small-angle scattering can provide valuable insights.

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 (τα) were measured by dielectric spectroscopy, and the Gibbs free energy (ΔG) and entropy (ΔS) difference between the crystalline and amorphous states were obtained by DSC. The temperature dependence of the crystallization induction time (τ0(T)) is a function of the thermodynamic activation barrier and the frequency of "attempted jumps" (1/τα(T)) to overcome the barrier. Even though the four model compounds exhibited very similar molecular mobility (relaxation time) over a wide range of temperatures, their crystallization propensities were very different. The observed difference in crystallization propensity was explained in terms of the difference in the thermodynamic barrier, and it is correlated to the empirical relation (TΔS3)/ΔG2.

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. The coamorphous systems exhibited exceptional physical stability and resisted crystallization at (i) elevated temperatures (>100 °C) and (ii) accelerated storage conditions, 40 °C/75% relative humidity for 15 months. The dissolution performance of each coamorphous system was compared with the respective crystalline drug based on the area under the curve (AUC) of the concentration-time profiles. A 25-fold increase in AUC was observed in the PYR-CA coamorphous system. The solubility enhancement is attributed not only due to drug amorphization but also due to solubilization by CA. The supramolecular synthon approach, through a drug-CA interaction, yielded physically stable coamorphous systems with enhanced aqueous drug solubility.

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.

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; C15H10I4NNaO4·5H2O). 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. Under hermetically sealed conditions (40 °C) hygroscopic excipients such as povidone induced partial dehydration of LSP to form levothyroxine sodium monohydrate. When stored at 40 °C/75% RH, acidic excipients induced measurable disproportionation of LSP resulting in the formation of levothyroxine (free acid). HPLC analyses of drug-excipient mixtures revealed that lactose monohydrate, microcrystalline cellulose, and croscarmellose sodium caused pronounced chemical decomposition of LSP. On the other hand, magnesium stearate, sodium stearyl fumarate, and alkaline pH modifiers did not affect the physical and chemical stability of the API following storage at 40 °C/75% RH. HPLC, being a solution based technique, revealed chemical decomposition of the API, but the technique was insensitive to physical transformations. Excipient properties such as hygroscopicity and microenvironmental acidity were identified to be critical determinants of both physical and chemical stability of LSP in a drug product. For drugs exhibiting both physical and chemical transformations, simultaneous solid-state and solution based analyses will enable comprehensive stability evaluation.

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. (ii) In a solution buffered with histidine, where there was no pH shift due to buffer salt crystallization. (iii) At different concentrations of LDH so as to determine the self-stabilizing ability of LDH. The change in LDH tetrameric conformation was measured by small-angle neutron scattering (SANS). The pH of the phosphate buffer solutions was monitored as a function of temperature to quantify the pH shift. The conditions of buffer component crystallization from solution were identified using low-temperature X-ray diffractometry. Dynamic light scattering (DLS) enabled us to determine the effect of freeze-thawing on the protein aggregation behavior. LDH, at a high concentration (1000 µg/mL; buffer concentration 10 mM), has a pronounced self-stabilizing effect and did not aggregate after five freeze-thaw cycles. At lower LDH concentrations (10 and 100 µg/mL), only with the selection of an appropriate buffer, irreversible aggregation could be avoided. While SANS provided qualitative information with respect to protein conformation, the insights from DLS were quantitative with respect to the particle size of the aggregates. SANS is the only technique which can characterize the protein both in the frozen and thawed states.

Characterizing Drug-Polymer Interactions in Aqueous Solution with Analytical Ultracentrifugation.

We present a new approach for characterizing drug-polymer interactions in aqueous media, using sedimentation velocity analytical ultracentrifugation (AUC). We investigated the potential interaction of ketoconazole (KTZ), a poorly water-soluble drug, with polyacrylic acid (PAA) and a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) in aqueous buffers. The effect of the polymer on the sedimentation coefficient of the drug was the observable metric. The drug alone, when subjected to AUC, exhibited a very narrow sedimentation peak at 0.2 Svedberg (S), in agreement with the expectation for a monomeric drug with a molar mass < 1000 Dalton. Conversely, the neat polymers showed broad profiles with higher sedimentation coefficients, reflecting their larger more heterogeneous size distributions. The sedimentation profiles of the drug-polymer mixtures were expectedly different from the profile of the neat drug. With KTZ-Soluplus, a complete shift to faster sedimentation times (indicative of an interaction) was observed, while with KTZ-PAA, a split peak indicated the existence of the drug in both free and interacting states. The sedimentation profile of carbamazepine, a second model drug, in the presence of hydroxypropyl methyl cellulose acetate succinate (HPMCAS, another polymer) revealed multiple "populations" of drug-polymer species, very similar to the sedimentation profile of neat HPMCAS. The interactions probed by AUC were compared with the results from isothermal titration calorimetry. In vitro dissolution tests performed on amorphous solid dispersions prepared with the same drug-polymer pairs suggested that the interactions may play a role in prolonging drug supersaturation. The results show the possibility of characterizing drug-polymer interactions in aqueous solution with high hydrodynamic resolution, addressing a major challenge frequently encountered in the mechanistic investigations of the dissolution behavior of amorphous solid dispersions.

The Influence of the Strength of Drug-Polymer Interactions on the Dissolution of Amorphous Solid Dispersions.

In an earlier report, ionic interactions between ketoconazole (KTZ), a weakly basic drug, and poly(acrylic acid) (PAA), an anionic polymer, resulted in a dramatic decrease in molecular mobility as well as reduced crystallization propensity of amorphous solid dispersion (ASD) in the solid state. On the other hand, weaker dipole-dipole interactions between KTZ and polyvinylpyrrolidone (PVP) resulted in ASDs with higher crystallization propensity (Mistry Mol Pharm., 2015, 12 (9), 3339-3350). In this work, we investigated the behavior of the ketoconazole (KTZ) solid dispersions in aqueous media. In vitro dissolution tests showed that the PAA ASD maintained the level of supersaturation for a longer duration than the PVP ASD at low polymer contents (4-20% w/w polymer). Additionally, the PAA ASDs were more resistant to drug crystallization in aqueous medium when measured with synchrotron X-ray diffractometry. Two-dimensional 1H nuclear Overhauser effect spectroscopy (NOESY) NMR cross peaks between ketoconazole and PAA confirmed the existence of drug-polymer interactions in D2O. The interaction was accompanied by a reduced drug diffusivity as monitored by 2D diffusion ordered spectroscopy (DOSY) NMR and enthalpy-driven when characterized by isothermal titration calorimetry (ITC). On the other hand, drug-polymer interactions were not detected between ketoconazole and PVP in aqueous solution, with NOESY, DOSY, or ITC. The results suggest that interactions that stabilize ASDs in the solid state can also be relevant and important in sustaining supersaturation in solution.

Modulation of Microenvironmental Acidity: A Strategy to Mitigate Salt Disproportionation in Drug Product Environment.

Disproportionation of pioglitazone hydrochloride (PioHCl), leading to the free base formation, was observed in tablet formulations containing basic excipients such as magnesium stearate (Koranne et al, Mol. Pharmaceutics, 2017, 14, 1133-1144). The nature and concentration of excipients, by modulating the microenvironmental acidity (measured as pHeq), governed the disproportionation reaction. In the current work, we hypothesized that the addition of an organic acid, by lowering the pHeq, can stabilize PioHCl. Powder blends containing PioHCl, magnesium stearate and each oxalic, maleic, tartaric, fumaric, and glutaric acid were stored at 40 °C/75% RH for 15 days. The concentration of crystalline free base, a product of the disproportionation reaction, was quantified using synchrotron radiation. The pHeq of the powder blends was measured via ionization of probe molecules deposited on the surface. In general, the stronger the acid, the lower the pHeq of the formulation blend and more effective it was in stabilizing PioHCl and preventing disproportionation. Thus, controlling the microenvironmental acidity in a rational and systematic way provided an avenue to mitigate excipient-induced salt disproportionation. Even when the lattice of PioHCl was activated by milling, it remained stable in the presence of acid. The amount of water sorbed during tablet storage provided an indirect measure of the disproportionation.

t-Butanol Enables Dual Functionality of Mannitol: A Cryoprotectant in Frozen Systems and Bulking Agent in Freeze-Dried Formulations.

The effect of tertiary butyl alcohol (TBA) as a cosolvent on the phase behavior of mannitol in frozen and freeze-dried systems was characterized using differential scanning calorimetry (DSC) and X-ray diffractometry (XRD; laboratory and synchrotron sources). Solutions of mannitol (2 and 5% w/w) in TBA-water systems of different compositions (5 to 30% w/w TBA) were characterized, both during cooling and warming using DSC and XRD. At and below the TBA-water eutectic composition (22.5% w/w TBA), mannitol crystallization was completely inhibited in the frozen state, while it crystallized as anhydrous δ-mannitol in the final lyophile. The presence of mannitol did not affect the phase behavior of TBA. The ability of mannitol to serve as a cryoprotectant in frozen solutions, and as a bulking agent in final lyophile was evaluated using human serum albumin (HSA) as a model protein. When HSA in a TBA (5% w/w)-water solution containing mannitol (2% w/w) was freeze-thawed or freeze-dried, there was no evidence of HSA aggregation. Thus, when TBA was used as a cosolvent, mannitol exhibited dual functionality, serving as a cryoprotectant in frozen solutions and as a bulking agent in the final lyophile.

Stabilization of Amorphous Drugs by Polymers: The Role of Overlap Concentration (C*).

Amorphous solid dispersions (ASDs), in which polymers are admixed with a drug, retard or inhibit crystallization of the drug, increasing the drug's apparent solubility and oral bioavailability. To date, there are no guidelines regarding how much polymer should be added to stabilize the amorphous form of the drug. We hypothesized that only drug that is not within a "sphere of influence" of a polymer chain is able to nucleate and form crystals and that the degree of crystallization should depend primarily on the ratio C/C*, where C is the polymer concentration and C* is the overlap concentration. We tested this hypothesis by quenching dispersions of polyvinylpyrrolidone (PVP) dissolved in molten felodipine (FEL) or indomethacin (IMC) at four molecular weights of PVP. For each molecular weight of PVP, C* in the drug (as solvent) was determined by dynamic light scattering and intrinsic viscosity. The enthalpy of fusion (ΔHf), determined by DSC, was used to measure the fraction of drug that crystallized in an ASD. It was found, roughly, that ΔHf/ΔHf,C=0 = f(C/C*) and that no crystallization occurred when C > C*. XRD also showed that crystallization was completely inhibited up to ∼Tg + 75 °C when the polymer concentration was above C*. Our results suggest that stabilization of amorphous drugs can be achieved by incorporating a polymer just above C*, which is much lower than polymer concentrations customarily used in ASDs. This work reveals the importance of C* in selecting polymer concentrations when formulating drugs as ASDs.

Partial Dehydration of Levothyroxine Sodium Pentahydrate in a Drug Product Environment: Structural Insights into Stability.

Levothyroxine sodium pentahydrate (LSP; C15H10I4NNaO4·5H2O) gradually loses one molecule of water of crystallization as the water vapor pressure is decreased from 90% to 15% RH (40 °C), a behavior characteristic of nonstoichiometric hydrates. LSP loses four molecules of water of crystallization to form levothyroxine sodium monohydrate (LSM; C15H10I4NNaO4·H2O) under realistic storage conditions (40 °C/0% RH for 3 h). The crystal structure of LSP was determined following which the specimen was partially dehydrated in situ to form LSM. The crystal structure of LSM provided insight into its potential for high reactivity. Thus, its presence in a drug product is undesirable. In LSP-oxalic acid mixtures stored in a hermetic container at 40 °C, there was moisture transfer from drug to excipient. Synchrotron X-ray diffractometry revealed dehydration of LSP resulting in LSM, while anhydrous oxalic acid transformed to its dihydrate. In formulations of LSP, chemical degradation of levothyroxine sodium may be preceded by its partial dehydration.

Formation of Indomethacin-Saccharin Cocrystals during Wet Granulation: Role of Polymeric Excipients.

Formulation of a cocrystal into a solid pharmaceutical dosage form entails numerous processing steps during which there is risk of dissociation. In an effort to reduce the number of unit operations, we have attempted the in situ formation of an indomethacin-saccharin (INDSAC) cocrystal during high-shear wet granulation (HSWG). HSWG of IND (poorly water-soluble drug) and SAC (coformer), with polymers (granulating agents), was carried out using ethanol as the granulation liquid and yielded INDSAC cocrystal granules. Therefore, cocrystal formation and granulation were simultaneously accomplished. Our objectives were to (i) evaluate the influence of polymers on cocrystal formation kinetics during wet granulation and (ii) mechanistically understand the role of polymers in facilitating the cocrystal formation. Polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), and polyethylene oxide (PEO) were chosen to investigate the influence of soluble polymers. The cocrystal formation kinetics was influenced by the polymer (PVP < HPC < PEO) and its concentration. The interaction of the polymer with cocrystal components inhibited the cocrystal formation. Complete cocrystal formation was observed in the presence of PEO, a polymer which does not interact with IND and SAC.