The role of alkyl chain length in the melt and solution crystallization of paliperidone aliphatic prodrugs.

Fatty acid-derivative prodrugs have been utilized extensively to improve the physicochemical, biopharmaceutical and pharmacokinetic properties of active pharmaceutical ingredients. However, to our knowledge, the crystallization behavior of prodrugs modified with different fatty acids has not been explored. In the present work, a series of paliperidone aliphatic prodrugs with alkyl chain lengths ranging from C4 to C16 was investigated with respect to crystal structure, crystal morphology and crystallization kinetics. The paliperidone derivatives exhibited isostructural crystal packing, despite the different alkyl chain lengths, and crystallized with the dominant (100) face in both melt and solution. The rate of crystallization for paliperidone derivatives in the melt increases with alkyl chain length owing to greater molecular mobility. In contrast, the longer chains prolong the nucleation induction time and reduce the crystal growth kinetics in solution. The results show a correlation between difficulty of nucleation in solution and the interfacial energy. This work provides insight into the crystallization behavior of paliperidone aliphatic prodrugs and reveals that the role of alkyl chain length in the crystallization behavior has a strong dependence on the crystallization method.

Effect of organic acids on the solid-state polymorphic phase transformation of piracetam.

Metastable polymorphs are frequently used in oral solid dosage forms to enhance the absorption of poorly water-soluble drug compounds. However, the solid phase transformation from the metastable polymorph to the thermodynamically stable polymorph during manufacturing or storage poses a major challenge for product development and quality control. Here, we report that low-content organic acids can exhibit distinct effects on the solid-state polymorphic phase transformation of piracetam (PCM), a nootropic drug used for memory enhancement. The addition of 1 mol% citric acid (CA) and tricarballylic acid (TA) can significantly inhibit the phase transformation of PCM Form I to Form II, while glutaric acid (GA) and adipic acid (AA) produce a minor effect. A molecular simulation shows that organic acid molecules can adsorb on the crystal surface of PCM Form I, thus slowing the movement of molecules from the metastable form to the stable form. Our study provides deeper insights into the mechanisms of solid-state polymorphic phase transformation of drugs in the presence of additives and facilitates opportunities for controlling the stability of metastable pharmaceuticals.

Advances in the development of amorphous solid dispersions: The role of polymeric carriers.

Amorphous solid dispersion (ASD) is one of the most effective approaches for delivering poorly soluble drugs. In ASDs, polymeric materials serve as the carriers in which the drugs are dispersed at the molecular level. To prepare the solid dispersions, there are many polymers with various physicochemical and thermochemical characteristics available for use in ASD formulations. Polymer selection is of great importance because it influences the stability, solubility and dissolution rates, manufacturing process, and bioavailability of the ASD. This review article provides a comprehensive overview of ASDs from the perspectives of physicochemical characteristics of polymers, formulation designs and preparation methods. Furthermore, considerations of safety and regulatory requirements along with the studies recommended for characterizing and evaluating polymeric carriers are briefly discussed.

Mechanistic Insight of Polymer Effects on the Kinetic of Solution-Mediated Phase Transformation of Nitrofurantoin Anhydrate to Monohydrate.

PURPOSE: Nitrofurantoin is an effective antibacterial drug for the treatment of lower urinary tract infection. However, the anhydrate form can easily transform to the less soluble hydrate form (monohydrate) during dissolution, resulting in a reduction of dissolution rate and oral bioavailability. Therefore, inhibition of phase transformation is vital to stabilize the quality of drugs. METHODS: In this work, the potential of polyethylene glycol (PEG 8000), polyvinyl pyrrolidone (PVP K30), poloxamer 188 and hydroxypropyl methylcellulose (HPMC) to inhibit the hydration of nitrofurantoin during dissolution was investigated by experimental and simulation approaches. RESULTS: The rates of phase transformation were decreased in the presence of PEG 8000 and poloxamer 188, and PVP K30 and HPMC completely inhibited the phase transformation of anhydrate. The abundant hydrogen bond donor and acceptor groups of PVP and HPMC may easily establish intermolecular interactions with nitrofurantoin molecules, accounting for stronger inhibition of nucleation. Besides, the molecular dynamic simulation further indicated the formation of more extensive interactions between PVP K30 (or HPMC) and the (111) face of monohydrate, suggesting that the strong absorption of polymers on the surface and thus block the sites for incorporation of new growth. CONCLUSION: This study provides a mechanistic insight into the inhibition of nitrofurantoin hydration by polymeric additives, which helps design formulations and improve the physical stability of anhydrate.

Melt Crystallization of Celecoxib-Carbamazepine Cocrystals with the Synchronized Release of Drugs.

PURPOSE: The fixed-dose combination drug products have been increasingly used to treat some complex diseases. A cocrystal containing two therapeutic components, named as a drug-drug cocrystal, is an ideal solid form to formulate as a fixed-dose combination product. The aim of the study is to prepare celecoxib-carbamazepine (CEL-CBZ) cocrystals by melt crystallization to achieve the synchronized release of drugs. METHOD: The crystal structure of the CEL-CBZ cocrystal was determined from the cocrystals harvested from melt by single crystal X-ray diffraction. The binary phase diagram and crystal growth kinetics of the CEL-CBZ cocrystal from melt were studied to optimize the process parameters of hot-melt extrusion for manufacturing large-scale cocrystals. The intrinsic dissolution rate studies were conducted to compare the dissolution profiles of drugs in the cocrystal and their individual forms. RESULT: The CEL-CBZ cocrystal crystallized in the triclinic space group with one CEL and one CBZ molecule in the asymmetric unit. The crystallization of CEL-CBZ cocrystals were observed both in the supercooled liquid and glassy state. The formation of drug-drug cocrystals significantly alter the intrinsic dissolution rates of the parent drugs to favor the synchronized release. CONCLUSION: Melt crystallization is an alternative, efficient and eco-friendly approach for preparing drug-drug cocrystals on a large scale. The synchronized drug release by drug-drug cocrystals can be used to modulate the release profiles of parent drugs in the fixed-dose combination products.

Modulation of Solid-State Chemical Stability of Gabapentin by Pyridinecarboxylic Acid.

PURPOSE: Gabapentin (GBP) is an anticonvulsant drug with poor chemical stability that is particularly sensitive to heat and mechanical stress, which can lead to intramolecular lactamization. The purpose of this study was to enhance the chemical stability of GBP by cocrystallization with organic acids. METHOD: Two novel multicomponent crystals, GBP-2,6-pyridinedicarboxylic acid salt (GBP-2,6PDA salt) and GBP-2,5-pyridinedicarboxylic acid cocrystal (GBP-2,5PDA cocrystal) were synthesized and characterized by various solid-state analytical techniques. The degradation behavior of GBP, GBP-2,6PDA salt and GBP-2,5PDA cocrystals were evaluated under thermal and mechanical stresses. RESULT: Under thermal and mechanical stresses, GBP-2,5PDA cocrystals were found to undergo severer degradation than GBP-2,6PDA salt and neat GBP. GBP-2,6PDA salt exhibited superior chemical stability compared to the others. Furthermore, the crystal structure revealed that the order of atomic distance between the carboxyl group (C7) and amino group (N12) of GBP is as follows: GBP-2,5PDA cocrystal < GBP < GBP-2,6PDA salt, which is consistent with the chemical stability of GBP in different solid forms. Therefore, we believe that the distance between C7 and N12, the reaction active sites leading to dehydrative condensation of GBP, is a key factor determining the chemical stability of GBP in the solid state. CONCLUSIONS: These results provide a potential method to improve the chemical stability of GBP during the manufacturing process and storage.

Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications.

Pharmaceutical cocrystals are multicomponent systems in which at least one component is an active pharmaceutical ingredient and the others are pharmaceutically acceptable ingredients. Cocrystallization of a drug substance with a coformer is a promising and emerging approach to improve the performance of pharmaceuticals, such as solubility, dissolution profile, pharmacokinetics and stability. This review article presents a comprehensive overview of pharmaceutical cocrystals, including preparation methods, physicochemical properties, and applications. Furthermore, some examples of drug cocrystals are highlighted to illustrate the effect of crystal structures on the various aspects of active pharmaceutical ingredients, such as physical stability, chemical stability, mechanical properties, optical properties, bioavailability, sustained release and therapeutic effect. This review will provide guidance for more efficient design and manufacture of pharmaceutical cocrystals with desired physicochemical properties and applications.

Melt Crystallization of Indomethacin Polymorphs in the Presence of Poly(ethylene oxide): Selective Enrichment of the Polymer at the Crystal-Liquid Interface.

Additives have been known to influence the crystallization behavior of amorphous pharmaceuticals. In this study, the semicrystalline polymer, poly(ethylene oxide) (PEO), exhibited a different impact on the crystal growth kinetics of indomethacin (IMC) polymorphs grown from the melt. Polarized light microscopy and Raman microscopy were employed to reveal the differences in phase separation occurring at the crystal-liquid interface of IMC polymorphs in the presence of PEO. It was found that at the same condition of melt crystallization PEO could be significantly enriched at the crystal growth front of IMC γ and α forms but not at that of the δ form. The local content of PEO at the growth front was proposed to correlate with the solubility of IMC polymorphs in the molten PEO. The distinct drug-polymer distribution at the crystal-liquid interface of IMC polymorphs could have different impacts on the thermodynamic and kinetic factors in the process of crystallization, resulting in different enhancements of crystal growth rates for the polymorphs. This study is beneficial to understanding the crystallization behavior of polymorphic drugs in the presence of polymeric additives, and more attention needs to be focused on the interfacial phenomena during crystal growth.

Enhanced Physical Stability and Synchronized Release of Febuxostat and Indomethacin in Coamorphous Solids.

Coamorphous formulation, a homogeneous monophasic amorphous system composed of multiple components, has been demonstrated as an effective approach for delivering drugs with poor aqueous solubility. In this study, we prepared the coamorphous system composed of two poorly soluble drugs febuxostat (FEB) and indomethacin (IMC) by using cryogenic milling. The combination of these two drugs in the coamorphous form can attain a synergistic effect, especially on gout therapy. Coamorphous solid of FEB and IMC in 1:1 molar ratio exhibited superior physical stability compared with the individual amorphous components, as evidenced by X-ray powder diffractions after 30 days of storage at ambient and elevated temperature. In addition, the FEB-IMC coamorphous system has been demonstrated to show enhanced dissolution performance. The intrinsic dissolution rates of two components in the coamorphous system exhibited the synchronized drug release. Based on the FT-IR spectroscopy, the excellent physical stability and synchronized release of FEB-IMC coamorphous system could be attributed to the heterodimer structure formed by strong hydrogen bonding interactions between these drugs. Furthermore, the supersaturation potential of FEB-IMC coamorphous solids was also investigated through the cosolvent quenching method. The FEB-IMC coamorphous system can effectively inhibit the fast crystallization of FEB in the supersaturated solution. However, the maximum achievable supersaturation of IMC in the coamorphous system decreases to only one fifth of that achieved for the pure amorphous IMC. These results are relevant for understanding the physical stability and complex solution behaviors of the coamorphous formulation.

Investigating Permeation Behavior of Flufenamic Acid Cocrystals Using a Dissolution and Permeation System.

The dissolution and permeation of the cocrystals, flufenamic acid-nicotinamide (FFA-NIC) and flufenamic acid-theophylline (FFA-TP), have been investigated in the presence of two polymers, polyvinylpyrrolidone (PVP) and copolymer of vinylpyrrolidone/vinyl acetate (PVP-VA), using a dissolution/permeation (D/P) system. It showed that the types and concentrations of the polymers and their interactions with the coformers had significant effects on the dissolution and permeation of the FFA cocrystals. The role of PVP as a stabilizing agent was not altered in spite of its interaction with the coformer of NIC or TP, which was supported by the proportional flux rate of FFA to the dissolution performance parameter (DPP). With an appropriate PVP concentration, the maximal flux rate of FFA could be obtained for a given FFA cocrystal. The situation was complicated in the presence of PVP-VA. The role of PVP-VA could change because of its association with the coformers, i.e., from a stabilizing agent to a solubilization agent. In addition, PVP-VA reduced the flux rate of FFA, in contrast to its DPP for FFA cocrystals. Finally, 1H NMR provided evidence regarding the molecular interactions between FFA, coformers, and polymers at the atomic level and gave insight into the mechanism underlying the supersaturated solution and subsequent permeation behavior of the cocrystals.

Insight into Flufenamic Acid Cocrystal Dissolution in the Presence of a Polymer in Solution: from Single Crystal to Powder Dissolution.

Effects of three polymers, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and copolymer of vinylpyrrolidone/vinyl acetate (PVP-VA), on the dissolution behavior of the cocrystals of flufenamic acid with theophylline (FFA-TP CO) and nicotinamide (FFA-NIC CO) were investigated at multiple length scales. At the molecular level, the interactions of crystal surfaces with a polymer were analyzed by observing etching pattern changes using atomic force microscopy. At the macroscopic scale, dissolution rates of particular faces of a single crystal were determined by measurement of the physical retreat velocities of the faces using optical light microscopy. In the bulk experiments, the FFA concentration in a dissolution medium in the absence or presence of a polymer was measured under both sink and nonsink conditions. It has been found that the dissolution mechanisms of FFA-TP CO are controlled by the defect sites of the crystal surface and by precipitation of the parent drug FFA as individual crystals in the bulk fluid. In contrast, the dissolution mechanisms of FFA-NIC CO are controlled by surface layer removal and by a surface precipitation mechanism, where the parent drug FFA precipitates directly onto the surface of the dissolving cocrystals. Through controlling the dissolution environment by predissolving a polymer, PVP or PVP-VA, which can interact with the crystal surface to alter its dissolution properties, improved solubility, and dissolution rates of FFA-TP CO and FFA-NIC CO have been demonstrated.

Investigating the Influence of Polymers on Supersaturated Flufenamic Acid Cocrystal Solutions.

The development of enabling formulations is a key stage when demonstrating the effectiveness of pharmaceutical cocrystals to maximize the oral bioavailability for poorly water soluble drugs. Inhibition of drug crystallization from a supersaturated cocrystal solution through a fundamental understanding of the nucleation and crystal growth is important. In this study, the influence of the three polymers of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and a copolymer of N-vinly-2-pyrrodidone (60%) and vinyl acetate (40%) (PVP-VA) on the flufenamic acid (FFA) crystallization from three different supersaturated solutions of the pure FFA and two cocrystals of FFA-NIC CO and FFA-TP CO has been investigated by measuring nucleation induction times and desupersaturation rates in the presence and absence of seed crystals. It was found that the competition of intermolecular hydrogen bonding among drug/coformer, drug/polymer, and coformer/polymer was a key factor responsible for maintaining supersaturation through nucleation inhibition and crystal growth modification in a cocrystal solution. The supersaturated cocrystal solutions with predissolved PEG demonstrated more effective stabilization in comparison to the pure FFA in the presence of the same polymer. In contrast, neither of the two cocrystal solutions, in the presence of PVP or PVP-VA, exhibited a better performance than the pure FFA with the same predissolved polymer. The study suggests that the selection of a polymeric excipient in a cocrystal formulation should not be solely dependent on the interplay of the parent drug and polymer without considering the coformer effects.