Polymeric precipitation inhibitor as an effective trigger to convert supersaturated into supersaturable state in vivo.

The supersaturated state of the drug in vivo is thermodynamically unstable resulting in a delayed response and reduced efficacy. The use of polymeric precipitation inhibitor (PPI) has been demonstrated as an effective trigger for the conversion of supersaturated state to supersaturable state for improving solubilization, thermodynamic maintenance of drug concentration and oral absorption of poorly water-soluble compounds. PPI retards drug precipitation and provides a kinetically stabilized supersaturation state for an extended period in gastric and intestinal fluids. However, the selection of appropriate PPI and understanding its mechanism is a challenge for formulating a stable pharmaceutical formulation. The present review is aimed at understanding the intricacies of selecting PPIs and their applications in pharmaceutical formulations.

The Influence of Cellulosic Polymer's Variables on Dissolution/Solubility of Amorphous Felodipine and Crystallization Inhibition from a Supersaturated State.

The collective impact of cellulosic polymers on the dissolution, solubility, and crystallization inhibition of amorphous active pharmaceutical ingredients (APIs) is still far from being adequately understood. The goal of this research was to explore the influence of cellulosic polymers and incubation conditions on enhancement of solubility and dissolution of amorphous felodipine, while inhibiting crystallization of the drug from a supersaturated state. Variables, including cellulosic polymer type, amount, ionic strength, and viscosity, were evaluated for effects on API dissolution/solubility and crystallization processes. Water-soluble cellulosic polymers, including HPMC E15, HPMC E5, HPMC K100-LV, L-HPC, and MC, were studied. All cellulosic polymers could extend API dissolution and solubility to various extents by delaying crystallization and prolonging supersaturation duration, with their effectiveness ranked from greatest to least as HPMC E15 > HPMC E5 > HPMC K100-LV > L-HPC > MC. Decreased polymer amount, lower ionic strength, or higher polymer viscosity tended to decrease dissolution/solubility and promote crystal growth to accelerate crystallization. HPMC E15 achieved greatest extended API dissolution and maintenance of supersaturation from a supersaturated state; this polymer thus had the greatest potential for maintaining sustainable API absorption within biologically relevant time frames.

Rules and characteristics of crystallization inhibition of cellulose polymers against drugs in supersaturated states / 药学学报

This study aims to explore the characteristics of crystallization inhibition by cellulose polymers at the supersaturated states of drugs. The study was performed by simulating supersaturated process and preparing supersaturated drug solid, and was carried out by measuring the content of drugs at different time points using dissolution apparatus. The types, amounts, ionic intensity and viscosity of cellulose polymers were examined to assess the crystallization inhibition effect on BCS II class drug indomethacin. HPMC E15 exhibited the strongest crystallization inhibition effect. The more added, more obvious crystallization suppression was observed against indomethacin. The decrease in viscosity and increase in ionic intensity led to an enhanced inhibition. The research provides a scientific guide for the crystallization inhibition of supersaturated drug by cellulose polymers.

Research on the rules of crystallization inhibition of cellulose polymers against supersaturated drugs by solubility test / 中国药学杂志

OBJECTIVE: To explore the characteristics of crystallization inhibition by cellulose polymers against supersaturated drugs. METHODS: The biopharmaceutics classification system(BCS) II class drug indometacin was selected as the model drug.Supersaturated amorphous drug solid was prepared and the solubility of indometacin was measured. The types, added amounts, ionic intensity and viscosity of cellulose polymers were employed as influential factors to assess the crystallization inhibition effect of polymers against indometacin. RESULTS: HPMC E15 displayed the strongest crystallization inhibition effect. The crystallization inhibition was enhanced by adding larger amount of polymers, decreasing the viscosity of polymers and increasing the ionic intensity. CONCLUSION: The study is helpful to clarify the profiles that cellulose polymers inhibit the crystallization of drugs in supersaturated states. This research may provide scientific guide for the practical application of cellulose polymers for drug crystallization.

Supersaturated state of diazepam injection following dilution with infusion fluid.

BACKGROUND: Significant precipitation produced by the dilution of diazepam (DZP) injection with an infusion fluid is a great concern for the clinical practice. In this study, the precipitation behavior under different conditions was investigated. METHOD: For the sample preparation, DZP injections (Horizon injection and Cercine injection) were diluted with various infusion fluids (Saline, 5% glucose infusion fluid and Soldem 3A) at designated dilution ratios ranging from 1× to 40× (5 mg/mL to 0.125 mg/mL). In addition, to measure the solubility of DZP in the samples, the saturated solutions of DZP were prepared. The DZP concentrations in the samples were measured by high-performance liquid chromatography (HPLC). This study also investigated the precipitate using various analytical methods: infrared microscopy, (1)H-NMR, differential scanning calorimetry, and powder X-ray deflection. RESULTS: First, the compatibility of injection with infusion fluids was investigated. Significant precipitation occurred at dilution ratios ranging from 2× to 20×. No significant effects of formulations and infusion fluids on the compatibility were observed. The solubility of DZP was then further investigated. The concentration of DZP dissolved in the admixtures was higher than the solubility. This indicated that DZP existed in a supersaturated state in the infusion fluid admixtures. In the next phase of this study, the precipitate was investigated using various analytical methods. Results showed that the precipitate in infusion fluid admixtures was mostly composed of DZP, but also contained small amounts of the ingredients of DZP injection, such as benzoic acid and benzyl alcohol. CONCLUSIONS: This study clarified details of the precipitation occurring after dilution of DZP injection with infusion fluids. It is worth noting that DZP in an infusion admixture existed in a supersaturated state. These findings offer important insight into the clinical practice of DZP injection.

Effect of polymers and media type on extending the dissolution of amorphous pioglitazone and inhibiting the recrystallization from a supersaturated state.

Amorphous forms of crystalline drug are widely utilized for bioavailability enhancement of low solubility drugs in the pharmaceutical industry. Polymers have been found to be effective crystallization inhibitors for amorphous forms in solid states during storage or in liquid states during dissolution process. The dissolution and crystallization behaviors of these amorphous forms in the presence or absence of polymers are still far from adequately understood especially in different dissolution environments. The objective of this study was to investigate the effects of polymers and media type on extending the dissolution of amorphous pioglitazone and inhibiting the recrystallization from a supersaturated state. Polyvinylpyrrolidone K30 (PVPK30), polyvinylpyrrolidone K90 (PVPK90), polyethylene glycol 6000 (PEG6000), polyethylene-polypropylene glycol 188 (F-68), hydroxypropylmethylcellulose (HPMC) and beta-cyclodextrin (ß-CD) were employed to understand these behaviors changes because these polymers were used widely. Three solutions including neutral water and phosphate buffer solutions (PBS, pH6.8 and pH7.4) were adopted as dissolution media to determine the behaviors changes comprehensively. In the presence of polymers, dissolution and solubility were extended to different degrees in three media. Polymers can delay the crystallization routes dependently of the medium type. Buffer salts in media reduced the dissolution and accelerated the crystallization process. Crystallization inhibition of these polymers was strongly dependent on the type and pH of media. HPMC displayed the strongest crystallization inhibition effects, resulting in the greatest degree of maintaining a supersaturated state that can sustain most effectively for biologically relevant timeframes.

Evaluation of Carbamazepine (CBZ) Supersaturatable Self-Microemulsifying (S-SMEDDS) Formulation In-vitro and In-vivo.

The supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) represents a new thermodynamically stable formulation approach wherein it is designed to contain a reduced amount of surfactant and a water-soluble polymer (precipitation inhibitor or supersaturated promoter) to prevent precipitation of the drug by generating and maintaining a supersaturated state in-vivo. The supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) of CBZ was evaluated in-vitro and in-vivo. Three different formulations of CBZ were prepared and drug precipitation behavior, dissolution rate in-vitro and particle size distribution were evaluated. Studies on CaCO-2 permeability of three formulations were also carried out. Pharmacokinetic studies were conducted in beagle dogs with administration dose of 200mg to assess bioavailability in-vivo compared with commercial tablet. The results showed that the presence of a small amount of polymeric precipitation inhibitor (PVP) effectively sustained supersaturated state by retarding precipitation kinetics. The mean particle size after dispersion was about 33.7 nm and the release rate from S-SMEDDS was significantly higher than the commercial tablet in-vitro. S-SMEDDS formulation with precipitation inhibitor decreased impairment to cells due to a lower surfactant level compared to SMEDDS. The absorption of S-SMEDDS in-vivo resulted in about 5-fold increase in bioavailability compared with the commercial tablet and the reproducibility of plasma concentration profiles intra-individual was improved remarkably. This study demonstrates that S-SMEDDS technology provide an effective approach for improving the extent of absorption of poorly-soluble drugs with low level of surfactant.