Drug–polymer miscibility,interactions, and precipitation inhibition studies for the development of amorphous solid dispersions for the poorly soluble anticancer drug flutamide

The major goal of this research was to successfully formulate solid dispersion (SD) of the poorly soluble anticancer drug flutamide (FLT) using various hydrophilic polymers. Furthermore, to get more insight into SD, solid-state studies (miscibility and molecular interaction) were correlated with solution study (precipitation inhibition, dissolution). Hydrophilic polymers like PVP K90, HPMC, Eudragit EPO, and PEG 8000 were used at different drug-to-polymer w/w ratios. Solid-state miscibility studies were carried out using modulated differential scanning calorimetry (MDSC). SDs were prepared using solvent-evaporation technique and characterized by powder X-ray diffraction (PXRD) and MDSC. Infrared, Raman spectroscopy and molecular modeling were used to investigate drug-polymer interactions in the dispersions. Precipitation inhibition studies were carried out at various FLT-hydrophilic polymer ratios. Precipitation inhibition studies showed that PEG 8000 has the highest efficiency, followed by PVP K90, while HPMC and EPO showed no effect on precipitation inhibition. In the solid-state, MDSC of the physical mixture (PM) suggested that FLT is miscible to a greater extent with EPO and PEG 8000. Characterization of the amorphous dispersions using MDSC and PXRD concluded that FLT transformed from crystalline to amorphous form in the presence of PVP K90 and PEG 8000. Spectroscopic results confirmed stronger interaction of FLT with PVP K90 and PEG 8000, thereby confirming the in-solution precipitation and molecular modeling binding energy results. Amorphous dispersions formulated with PVP and PEG were stable and showed higher dissolution, an important property necessary to improve the physicochemical properties and drug delivery of poorly soluble anticancer drug FLT.     

Development of solid dispersions of β-lapachone in PEG and PVP by solvent evaporation method

β-lapachone (βlap) has shown potential use in various medical applications. However, its poor solubility has limited its systemic administration and clinical applications. The aim of this work is to develop solid dispersions of βlap using poly (ethylene glycol) (PEG 6000) and polyvinylpyrrolidone (PVP K30) as hydrophilic polymers and evaluate the dissolution rate in aqueous medium. Solid dispersions were prepared by solvent evaporation method using different weight ratios of βlap and hydrophilic polymer (1:1, 1:2, and 1:3). Characterization performed by differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy showed that βlap was molecularly dispersed within the polymer matrix. The in vitro dissolution tests showed an enhancement in the dissolution profile of βlap as solid dispersions prepared in both PVP and PEG, although the former showed better results. The drug:polymer ratio influenced βlap dissolution rate, as higher amounts of hydrophilic polymer led to enhanced drug dissolution. Thus, this study demonstrated that solid dispersions of βlap in PVP offers an effective way to overcome the poor dissolution of βlap.     

Part II: bioavailability in beagle dogs of nimodipine solid dispersions prepared by hot-melt extrusion

The aim of the present work was to investigate the in vitro dissolution properties and oral bioavailability of three solid dispersions of nimodipine. The solid dispersions were compared with pure nimodipine, their physical mixtures, and the marketed drug product Nimotop. Nimodipine solid dispersions were prepared by a hot-melt extrusion process with hydroxypropyl methylcellulose (HPMC, Methocel E5), polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA, Plasdone S630), and ethyl acrylate, methyl methacrylate polymer (Eudragit EPO). Previous studies of XRPD and DSC data showed that the crystallinity was not observed in hot-melt extrudates, two T(g)s were observed in the 30% and 50% NMD-HPMC samples, indicating phase separation. The weakening and shift of the N-H stretching vibration of the secondary amine groups of nimodipine as determined by FT-IR proved hydrogen bonding between the drug and polymers in the solid dispersion. The dissolution profiles of the three dispersion systems showed that the release was improved compared with the unmanipulated drug. Drug plasma concentrations were determined by HPLC, and pharmacokinetic parameters were calculated after orally administering each preparation containing 60 mg of nimodipine. The mean bioavailability of nimodipine was comparable after administration of the Eudragit EPO solid dispersion and Nimotop, but the HPMC and PVP/VA dispersions exhibited much lower bioavailability. However, the AUC(0-12 hr) values of all three solid dispersions were significantly higher than physical mixtures with the same carriers and nimodipine powder.     

Evaluation of hypromellose acetate succinate (HPMCAS) as a carrier in solid dispersions

The utility of hypromellose acetate succinate (HPMCAS), a cellulosic enteric coating agent, as a carrier in a solid dispersion of nifedipine (NP) was evaluated in comparison with other polymers, including hypromellose (HPMC), hypromellose phthalate (HPMCP), methacrylic acid ethyl acrylate copolymer (MAEA), and povidone (PVP). An X-ray diffraction study showed that the minimum amount of HPMCAS required to make the drug completely amorphous was the same as that of other cellulosic polymers, and less than that in dispersions using non-cellulosic polymers. Hypromellose acetate succinate showed the highest drug dissolution level from its solid dispersion in a dissolution study using a buffer of pH 6.8. This characteristic was unchanged after a storage test at high temperature and high humidity. The inhibitory effect of HPMCAS on recrystallization of NP from a supersaturated solution was the greatest among all the polymers examined. Further, the drug release pattern could be modulated by altering the ratio of succinoyl and acetyl moieties in the polymer chain. Our results indicate that HPMCAS is an attractive candidate for use as a carrier in solid dispersions.     

Dissolution rate enhancement,in vitro evaluation and investigation of drug release kinetics of chloramphenicol and sulphamethoxazole solid dispersions

Formulation of solid dispersions is one of the effective methods to increase the rate of solubilization and dissolution of poorly soluble drugs. Solid dispersions of chloramphenicol (CP) and sulphamethoxazole (SX) as model drugs were prepared by melt fusion method using polyethylene glycol 8000 (PEG 8000) as an inert carrier. The dissolution rate of CP and SX were rapid from solid dispersions with low drug and high polymer content. Characterization was performed using fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). FTIR analysis for the solid dispersions of CP and SX showed that there was no interaction between PEG 8000 and the drugs. Hyper-DSC studies revealed that CP and SX were converted into an amorphous form when formulated as solid dispersion in PEG 8000. Mathematical analysis of the release kinetics demonstrated that drug release from the various formulations followed different mechanisms. Permeability studies demonstrated that both CP and SX when formulated as solid dispersions showed enhanced permeability across Caco-2 cells and CP can be classified as well-absorbed compound when formulated as solid dispersions.     

Evaluation of solid dispersions of Clofazimine

Clofazimine (CLF) was formulated with polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP) as a solid solid dispersion (SSD) to increase the aqueous solubility and dissolution rate of the drug. Different molecular weights of PEG (1500, 4000, 6000, and 9000 Da) and PVP (14,000 and 44,000 Da) were used in different drug:carrier weight ratios (1:1, 1:5, and 1:9) and their effect on the dissolution performance of the drug was evaluated in USP Type 2 apparatus using 0.1 N HCl medium. The dissolution rate was compared with corresponding physical mixtures, a currently marketed soft gelatin capsule product, and free CLF. The effect of different methods of preparation (solvent/melt) on the dissolution rate of CLF was evaluated for PEG solid dispersions. Saturation solubility and phase solubility studies were carried out to indicate drug:carrier interactions in liquid state. Infrared (IR) spectroscopy and X-ray diffraction (XRD) were used to indicate drug:carrier interactions in solid state. Improvement in the drug dissolution rate was observed in solid dispersion formulations as compared to the physical mixtures. The dissolution rate improved with the decreasing weight fraction of the drug in the formulation. Polyvinyl pyrrolidone solid dispersion systems gave a better drug release profile as compared to the corresponding PEG solid dispersions. The effect of molecular weight of the PEG polymers did not follow a definite trend, while PVP 14,000 gave a better dissolution profile as compared to PVP 44,000. Improvement in saturation solubility of the drug in the solid dispersion systems was noted in all cases. Further, IR spectroscopy indicated drug:carrier interactions in solid state in one case and XRD indicated reduction in the crystallinity of CLF in another. It was concluded that solid-dispersion formulations of Clofazimine can be used to design a solid dosage form of the drug, which would have significant advantages over the currently marketed soft gelatin capsule dosage form.     

Evaluation of Solid Dispersions of Clofazimine

ABSTRACT

Clofazimine (CLF) was formulated with polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP) as a solid solid dispersion (SSD) to increase the aqueous solubility and dissolution rate of the drug. Different molecular weights of PEG (1500, 4000, 6000, and 9000 Da) and PVP (14,000 and 44,000 Da) were used in different drug:carrier weight ratios (1:1, 1:5, and 1:9) and their effect on the dissolution performance of the drug was evaluated in USP Type 2 apparatus using 0.1 N HCl medium. The dissolution rate was compared with corresponding physical mixtures, a currently marketed soft gelatin capsule product, and free CLF. The effect of different methods of preparation (solvent/melt) on the dissolution rate of CLF was evaluated for PEG solid dispersions. Saturation solubility and phase solubility studies were carried out to indicate drug:carrier interactions in liquid state. Infrared (IR) spectroscopy and X-ray diffraction (XRD) were used to indicate drug:carrier interactions in solid state. Improvement in the drug dissolution rate was observed in solid dispersion formulations as compared to the physical mixtures. The dissolution rate improved with the decreasing weight fraction of the drug in the formulation. Polyvinyl pyrrolidone solid dispersion systems gave a better drug release profile as compared to the corresponding PEG solid dispersions. The effect of molecular weight of the PEG polymers did not follow a definite trend, while PVP 14,000 gave a better dissolution profile as compared to PVP 44,000. Improvement in saturation solubility of the drug in the solid dispersion systems was noted in all cases. Further, IR spectroscopy indicated drug:carrier interactions in solid state in one case and XRD indicated reduction in the crystallinity of CLF in another. It was concluded that solid-dispersion formulations of Clofazimine can be used to design a solid dosage form of the drug, which would have significant advantages over the currently marketed soft gelatin capsule dosage form.     

Solubility advantage from amorphous etoricoxib solid dispersions

Objective: This study aimed to evaluate kinetic solubility advantage of amorphous etoricoxib solid dispersions prepared with three water soluble polymers and correlate it with solid state and supersaturated drug solution stabilization potential of these polymers.

Methods: Amorphous solid dispersions (ASDs) of etoricoxib were prepared with polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP) and hydroxyethyl cellulose (HEC) at 70:30w/w ratio and characterized for glass transition temperature (T_g), miscibility and intermolecular interactions. Kinetic solubility profiles of amorphous etoricoxib and its ASDs were determined in water at 37 °C. Solid-state stability was assessed by enthalpy relaxation studies at a common degree of undercooling of around 19.0 °C at 0% RH. Recrystallization behavior of supersaturated drug solution was evaluated in the absence and presence of pre-dissolved polymer at 37 °C.

Results: Amorphous etoricoxib exhibited rapid solid-to-solid transition to yield a solubility advantage of merely 1.5-fold in water. Among the ASDs, etoricoxib-PVP dispersion exhibited maximal “peak” (2-fold) and “plateau” (1.8-fold) solubility enhancement, while etoricoxib-PVA dispersion could only sustain the “peak” solubility achieved by amorphous etoricoxib. In contrast, etoricoxib-HEC dispersion displayed no solubility advantage. The rank order for solid state and supersaturated solution stabilization followed a similar trend of amorphous etoricoxib?Conclusion: Dissolution behavior of ASDs is influenced by concomitantly occurring solid phase changes, thus understanding these processes independently can enable assessment of the predominant route of drug crystallization and stabilization by the polymer.     

Lonidamine Solid Dispersions: In Vitro and In Vivo Evaluation

ABSTRACT

Solid dispersions of lonidamine in PEG 4000 and PVP K 29/32 were prepared by the spray-drying method. Then, the binary systems were studied and characterized using differential scanning calorimetry, hot stage microscopy, and x-ray diffractometry. In vitro dissolution studies of the solid dispersed powders were performed to verify if any lonidamine dissolution rate or water solubility improvement occurred. In vivo tests were carried out on the solid dispersions and on the cyclodextrin inclusion complexes to verify if this lonidamine water solubility increase was really able to improve the in vivo drug plasma levels. Drug water solubility was increased by the solid dispersion formation, and the extent of increase depended on the polymer content of the powder. The greater increase of solubility corresponded to the highest content of polymer. Both the solid dispersions and the cyclodextrin complexes were able to improve the in vivo bioavailability of the lonidamine when administered per os. Particularly, the AUC of the drug plasma levels was increased from 1.5 to 1.9-fold depending on the type of carrier.     

Lonidamine solid dispersions: in vitro and in vivo evaluation

Solid dispersions of lonidamine in PEG 4000 and PVP K 29/32 were prepared by the spray-drying method. Then, the binary systems were studied and characterized using differential scanning calorimetry, hot stage microscopy, and x-ray diffractometry. In vitro dissolution studies of the solid dispersed powders were performed to verify if any lonidamine dissolution rate or water solubility improvement occurred. In vivo tests were carried out on the solid dispersions and on the cyclodextrin inclusion complexes to verify if this lonidamine water solubility increase was really able to improve the in vivo drug plasma levels. Drug water solubility was increased by the solid dispersion formation, and the extent of increase depended on the polymer content of the powder. The greater increase of solubility corresponded to the highest content of polymer. Both the solid dispersions and the cyclodextrin complexes were able to improve the in vivo bioavailability of the lonidamine when administered per os. Particularly, the AUC of the drug plasma levels was increased from 1.5 to 1.9-fold depending on the type of carrier.     

Eudragit Microcapsules of Nifedipine and Its Dispersions in HPMC-MCC: Physicochemical Characterization and Drug Release Studies

Nifedipine and its solid dispersions in hydroxypropyl methyl cellulose-microcrystalline cellulose (HPMC-MCC) were microencapsulated with Eudragit RL PM by an emulsion solvent evaporation method. The microcapsules are spherical, discrete, free flowing, and covered with a continuous coating of the polymer. XRD and DTA indicated the presence of nifedipine in solution form in the solid dispersions and their microcapsules. No chemical interaction between nifedipine and excipients in the microcapsules was observed. Nifedipine as such and its microcapsules gave very slow release because of its highly crystalline nature and poor solubility. Solid dispersion in HPMC-MCC gave fast and rapid dissolution of nifedipine. When these solid dispersions were microencapsulated a slow, controlled, and complete release over a period of 12 hr was observed from the resulting microcapsules. Drug release depended on the proportion of HPMC-MCC in the solid dispersion used as a core, coat, core ratio, and size of the microcapsules. Release was independent of pH and ionic strength. Drug release was governed by diffusion rate and followed first-order kinetics.     

Classification of solid dispersions: correlation to (i) stability and solubility (ii) preparation and characterization techniques

Solid dispersion has been a topic of interest in recent years for its potential in improving oral bioavailability, especially for poorly water soluble drugs where dissolution could be the rate-limiting step of oral absorption. Understanding the physical state of the drug and polymers in solid dispersions is essential as it influences both the stability and solubility of these systems. This review emphasizes on the classification of solid dispersions based on the physical states of drug and polymer. Based on this classification, stability aspects such as crystallization tendency, glass transition temperature (T_g), drug polymer miscibility, molecular mobility, etc. and solubility aspects have been discussed. In addition, preparation and characterization methods for binary solid dispersions based on the classification have also been discussed.     

Carbamazepine and Polyethylene Glycol Solid Dispersions: Preparation,in Vitro Dissolution,and Characterization

Abstract

The objective of this study was to prepare solid dispersions of carbamazepine (CBZ) using polyethylene glycol (PEG) 4000 and PEG 6000, measure the dissolution, and characterize using x-ray diffraction, DSC, and IR spectroscopy. Solid dispersions were prepared by either the melt or solvent methods. A comparison of dissolution profiles of the solid dispersions indicated dramatic increases in the rate and extent of CBZ dissolution from solid dispersions. The dissolution of physical mixtures provided evidence of the solubilizing effects of PEGs. Untreated CBZ exhibited 10.09 ± 2.92% dissolution in 10 min (D_l0); whereas, a melt of PEG 6000 and CBZ at a ratio of 6: 1 provided 36.49 ± 1.97% and a melt of PEG 4000 and CBZ at a ratio of 6: 1 gave a D₁₀ of 23.59 ± 1.45%. The rate and extent of dissolution of CBZ were significantly higher when blends of the PEGs were employed to prepare solid dispersion. The melt method provided significantly higher rate and extent of dissolution of CBZ than the solvent method. Also, the rate and extent of dissolution of CBZ were significantly greater when the solid dispersion was cooled at room temperature as opposed to with ice (faster). X-ray diffractometry revealed almost a complete loss of crystallinity of CBZ in solid dispersions. IR spectrometry indicated an increase in amorphocity of the PEGs after melting. IR spectra suggested that no complexation occurred between the PEGs and CBZ. Alterations in the crystallinity of the system were also supported by the DSC thermograms. Decreasing heats of fusion implied decrease in crystallinity, which would be expected to provide greater dissolution rates. Peak melting temperatures obtained from the thermograms ruled out the possibility of the formation of a eutectic mixture. However, the formation of solid solution could also be a possible mechanism for the increase in dissolution.     

Carbamazepine and Polyethylene Glycol Solid Dispersions: Preparation, in Vitro Dissolution, and Characterization

The objective of this study was to prepare solid dispersions of carbamazepine (CBZ) using polyethylene glycol (PEG) 4000 and PEG 6000, measure the dissolution, and characterize using x-ray diffraction, DSC, and IR spectroscopy. Solid dispersions were prepared by either the melt or solvent methods. A comparison of dissolution profiles of the solid dispersions indicated dramatic increases in the rate and extent of CBZ dissolution from solid dispersions. The dissolution of physical mixtures provided evidence of the solubilizing effects of PEGs. Untreated CBZ exhibited 10.09 ± 2.92% dissolution in 10 min (D_l0); whereas, a melt of PEG 6000 and CBZ at a ratio of 6: 1 provided 36.49 ± 1.97% and a melt of PEG 4000 and CBZ at a ratio of 6: 1 gave a D₁₀ of 23.59 ± 1.45%. The rate and extent of dissolution of CBZ were significantly higher when blends of the PEGs were employed to prepare solid dispersion. The melt method provided significantly higher rate and extent of dissolution of CBZ than the solvent method. Also, the rate and extent of dissolution of CBZ were significantly greater when the solid dispersion was cooled at room temperature as opposed to with ice (faster). X-ray diffractometry revealed almost a complete loss of crystallinity of CBZ in solid dispersions. IR spectrometry indicated an increase in amorphocity of the PEGs after melting. IR spectra suggested that no complexation occurred between the PEGs and CBZ. Alterations in the crystallinity of the system were also supported by the DSC thermograms. Decreasing heats of fusion implied decrease in crystallinity, which would be expected to provide greater dissolution rates. Peak melting temperatures obtained from the thermograms ruled out the possibility of the formation of a eutectic mixture. However, the formation of solid solution could also be a possible mechanism for the increase in dissolution.     

Dissolution Rates of Carbamazepine and Nitrazepam Utilizing Sugar Solid Dispersion System

Abstract

The dissolution of carbamazepine and nitrazepam from Its solid dispersions using anhydrous lactose, mannitol, galactose, PEG 6000 and coprecipitate using polyvinylpyrrolidone (PVP) 40,000 was investigated. The dissolution process of capsules containing either carbamazepine or nitrazepam as solid dispersion or coprecipitate followed an apparent first order process. The combination of carbamazepine with sugars (mannitol, lactose, and galactose) caused, in every case, an increase in the dissolution rate of the drug. Carbamazepine-PVP coprecipitate gave the higher dissolution rate than that of the solid dispersions with sugars and PEG 6000. Nitrazepam-lactose system gave higher dissolution rate than the other dispersions and coprecipitate. This enhancement in dissolution rate was much more obvious for the solid dispersions and coprecipitate than for the physical mixtures.     

Eudragit Microcapsules of Nifedipine and Its Dispersions in HPMC-MCC: Physicochemical Characterization and Drug Release Studies

Abstract

Nifedipine and its solid dispersions in hydroxypropyl methyl cellulose-microcrystalline cellulose (HPMC-MCC) were microencapsulated with Eudragit RL PM by an emulsion solvent evaporation method. The microcapsules are spherical, discrete, free flowing, and covered with a continuous coating of the polymer. XRD and DTA indicated the presence of nifedipine in solution form in the solid dispersions and their microcapsules. No chemical interaction between nifedipine and excipients in the microcapsules was observed. Nifedipine as such and its microcapsules gave very slow release because of its highly crystalline nature and poor solubility. Solid dispersion in HPMC-MCC gave fast and rapid dissolution of nifedipine. When these solid dispersions were microencapsulated a slow, controlled, and complete release over a period of 12 hr was observed from the resulting microcapsules. Drug release depended on the proportion of HPMC-MCC in the solid dispersion used as a core, coat, core ratio, and size of the microcapsules. Release was independent of pH and ionic strength. Drug release was governed by diffusion rate and followed first-order kinetics.     

Production of advanced solid dispersions for enhanced bioavailability of itraconazole using KinetiSol® Dispersing

Objectives: To investigate the ability of KinetiSol® Dispersing to prepare amorphous solid dispersions of itraconazole using concentration-enhancing polymers. Methods: Concentration-enhancing nature of several cellulosic polymers (HPMC, hypromellose acetate succinate) was studied using a modified in vitro dissolution test. Solid dispersions were prepared by KinetiSol® Dispersing and characterized for solid-state properties using X-ray diffraction and differential scanning calorimetry. Potency and release characteristics were also assessed by high-performance liquid chromatography. Oral bioavailability of lead formulations was also assessed in animal models. Results: Screening studies demonstrated superior concentration-enhancing performance from the hypromellose acetate succinate polymer class. Data showed that stabilization was related to molecular weight and the degree of hydrophobic substitution on the polymer such that HF > MF ≈ LF, indicating that stabilization was achieved through a combination of steric hindrance and hydrophobic interaction, supplemented by the amphiphilic nature and ionization state of the polymer. Solid dispersions exhibited amorphous solid-state behavior and provided neutral media supersaturation using a surfactant-free pH change method. Rank-order behavior was such that LF > MF > HF. Addition of Carbopol 974P increased acidic media dissolution, while providing a lower magnitude of supersaturation in neutral media because of swelling of the high viscosity gel. In vivo results for both lead compositions displayed erratic absorption was attributed to the variability of gastrointestinal pH in the animals. Conclusions: These results showed that production of amorphous solid dispersions containing concentration-enhancing polymers through KinetiSol® Dispersing can provide improved oral bioavailability; however, additional formulation techniques must be developed to minimize variability associated with natural variations in subject gastrointestinal physiology.     

Enhancement of Dissolution and Bioavailability of Piroxicam in Solid Dispersion Systems

Solid dispersion systems of water-insoluble piroxicam in polyethylene glycol (PEG) 4000 and in urea were prepared by fusion and solvent methods and were characterized in this study. The in vitro dissolution studies showed that the dispersion systems containing piroxicam and PEG4000 or urea gave faster dissolution than the corresponding simple mixtures. The differential scanning calorimetry (DSC) study indicated that the piroxicam-PEG system prepared by the fusion method is a solid dispersion, while the piroxicam-urea system prepared by the solvent method is likely to be a solid solution of piroxicam in urea. The storage testings showed that all dispersions were stable, except that uptake of water during storage may occur in the PEG system. A single-dose study with rabbits showed that the dispersion systems provided statistically significant to a higher extent and rate of bioavailability than the corresponding physical mixture (p < 0.05).     

Enhancement of dissolution and bioavailability of piroxicam in solid dispersion systems

Solid dispersion systems of water-insoluble piroxicam in polyethylene glycol (PEG) 4000 and in urea were prepared by fusion and solvent methods and were characterized in this study. The in vitro dissolution studies showed that the dispersion systems containing piroxicam and PEG4000 or urea gave faster dissolution than the corresponding simple mixtures. The differential scanning calorimetry (DSC) study indicated that the piroxicam-PEG system prepared by the fusion method is a solid dispersion, while the piroxicam-urea system prepared by the solvent method is likely to be a solid solution of piroxicam in urea. The storage testings showed that all dispersions were stable, except that uptake of water during storage may occur in the PEG system. A single-dose study with rabbits showed that the dispersion systems provided statistically significant to a higher extent and rate of bioavailability than the corresponding physical mixture (p < 0.05).     

Part II: Bioavailability in Beagle Dogs of Nimodipine Solid Dispersions Prepared by Hot-Melt Extrusion

ABSTRACT

The aim of the present work was to investigate the in vitro dissolution properties and oral bioavailability of three solid dispersions of nimodipine. The solid dispersions were compared with pure nimodipine, their physical mixtures, and the marketed drug product Nimotop®. Nimodipine solid dispersions were prepared by a hot-melt extrusion process with hydroxypropyl methylcellulose (HPMC, Methocel E5), polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA, Plasdone S630®), and ethyl acrylate, methyl methacrylate polymer (Eudragit® EPO). Previous studies of XRPD and DSC data showed that the crystallinity was not observed in hot-melt extrudates, two T_gs were observed in the 30% and 50% NMD-HPMC samples, indicating phase separation. The weakening and shift of the N–H stretching vibration of the secondary amine groups of nimodipine as determined by FT-IR proved hydrogen bonding between the drug and polymers in the solid dispersion. The dissolution profiles of the three dispersion systems showed that the release was improved compared with the unmanipulated drug. Drug plasma concentrations were determined by HPLC, and pharmacokinetic parameters were calculated after orally administering each preparation containing 60 mg of nimodipine. The mean bioavailability of nimodipine was comparable after administration of the Eudragit® EPO solid dispersion and Nimotop®, but the HPMC and PVP/VA dispersions exhibited much lower bioavailability. However, the AUC_{0–12 hr} values of all three solid dispersions were significantly higher than physical mixtures with the same carriers and nimodipine powder.