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.

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.

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. In rapidly cooled (10 °C/min) aqueous binary solutions, P188 (10% w/v) was retained in the amorphous state. At slower cooling rates (0.5-5 °C/min), the extent of crystallization depended on the cooling rate. In ternary P188-trehalose-water systems (P188 4% w/v, trehalose 0-10% w/v), a concentration dependent inhibition of P188 crystallization was observed with increasing trehalose concentration. However, irrespective of trehalose concentration, annealing resulted in P188 crystallization. The presence of trehalose as well as the processing conditions (cooling rate and annealing) influenced the physical state of P188 at different stages of freezing and thawing. As the cooling rate decreased, the extent of P188 crystallization progressively increased. In presence of trehalose (≥4.0% w/v) crystallization of P188 (4.0% w/v) was inhibited and this effect could be reversed by annealing. Depending on the intended application, the physical form of P188 could be modulated, by annealing even in presence of a noncrystallizing solute.

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.

Role of Lattice Disorder in Water-Mediated Dissociation of Pharmaceutical Cocrystal Systems.

Our objective is to mechanistically understand the implications of processing-induced lattice disorder on  the stability of pharmaceutical cocrystals. Caffeine-oxalic acid (CAFOXA) and dicalcium phosphate anhydrate (DCPA) were the model cocrystal (drug) and excipient, respectively. Cocrystal-excipient mixtures were milled for short times (≤2 min) and stored at room temperature (RT)/75% RH. Milling-induced lattice disorder was quantified using powder X-ray diffractometry and gravimetric water sorption. Milling for even 10 s resulted in measurable disorder and an attendant tendency of the solid to sorb water. This was followed by  cocrystal-excipient interaction leading to dissociation. The proposed mechanism of cocrystal dissociation entails the following sequence: sorption of water by disordered regions, dissolution of CAFOXA and DCPA in the sorbed water, followed by proton transfer from the coformer (oxalic acid) to DCPA, and the formation of hydrates of caffeine and calcium oxalate. As such, CAFOXA is a robust cocrystal, stable even under elevated humidity conditions (RT/98% RH). However, in a drug product environment, routine pharmaceutical processing steps such as milling and compaction have the potential to induce sufficient disorder to render it unstable.

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.

Solid-State Characterization and Relative Formation Enthalpies To Evaluate Stability of Cocrystals of an Antidiabetic Drug.

The current study integrates formation enthalpy and traditional slurry experiments to quickly assess the physical stability of cocrystal drug substance candidates for their potential to support drug development. Cocrystals of an antidiabetic drug (GKA) with nicotinamide (NMA), vanillic acid (VLA), and ethyl vanillin (EVL) were prepared and characterized by powder X-ray diffractometry (PXRD), spectroscopic, and thermal techniques. The formation enthalpies of the cocrystals, and their physical mixtures (GKA + coformer) were measured by the differential scanning calorimetry (DSC) method reported by Zhang et al. [ Cryst. Growth Des. 2012 , 12 ( 8 ), 4090 - 4097 ]. The experimentally measured differences in the relative formation enthalpies obtained by integrating the heat flow of each cocrystal against the respective physical mixture were correlated to the physical stability of the cocrystals in the solid state. The relative formation enthalpies of all of the cocrystals studied suggest that the cocrystals are not physically stable at room temperature versus their physical mixtures. To further address relative stability, the cocrystals were slurried in 30% v/v aqueous ethanol, and it was observed that all of the cocrystals revert to GKA within 48 h at room temperature. The slurry experiments are consistent with the relative instability of the cocrystals with respect to their physical mixtures suggested by the DSC results.

Mechanistic Insight into Caffeine-Oxalic Cocrystal Dissociation in Formulations: Role of Excipients.

Caffeine-oxalic acid cocrystal, widely reported to be stable under high humidity, dissociated in the presence of numerous pharmaceutical excipients. In cocrystal-excipient binary systems, the water mediated dissociation reaction occurred under pharmaceutically relevant storage conditions. Powder X-ray diffractometry was used to identify the dissociated products obtained as a consequence of coformer-excipient interaction. The proposed cocrystal dissociation mechanism involved water sorption, dissolution of cocrystal and excipient in the sorbed water, proton transfer from oxalic acid to the excipient, and formation of metal salts and caffeine hydrate. In compressed tablets with magnesium stearate, the cocrystal dissociation was readily discerned from the appearance of peaks attributable to caffeine hydrate and stearic acid. Neutral excipients provide an avenue to circumvent the risk of water mediated cocrystal dissociation.