Characterization of Controlled Release Starch-Nimodipine Implant for Antispasmodic and Neuroprotective Therapies in the Brain.

Parenteral depot systems can provide a constant release of drugs over a few days to months. Most of the parenteral depot products on the market are based on poly(lactic acid) and poly(lactide-co-glycolide) (PLGA). Studies have shown that acidic monomers of these polymers can lead to nonlinear release profiles or even drug inactivation before release. Therefore, finding alternatives for these polymers is of great importance. Our previous study showed the potential of starch as a natural and biodegradable polymer to form a controlled release system. Subarachnoid hemorrhage (SAH) is a life-threatening type of stroke and a major cause of death and disability in patients. Nimotop® (nimodipine (NMD)) is an FDA-approved drug for treating SAH-induced vasospasms. In addition, NMD has, in contrast to other Ca antagonists, unique neuroprotective effects. The oral administration of NMD is linked to variable absorption and systemic side effects. Therefore, the development of a local parenteral depot formulation is desirable. To avoid the formation of an acidic microenvironment and autocatalytic polymer degradation, we avoided PLGA as a matrix and investigated starch as an alternative. Implants with drug loads of 20 and 40% NMD were prepared by hot melt extrusion (HME) and sterilized with an electron beam. The effects of HME and electron beam on NMD and starch were evaluated with NMR, IR, and Raman spectroscopy. The release profile of NMD from the systems was assessed by high-performance liquid chromatography. Different spectroscopy methods confirmed the stability of NMD during the sterilization process. The homogeneity of the produced system was proven by Raman spectroscopy and scanning electron microscopy images. In vitro release studies demonstrated the sustained release of NMD over more than 3 months from both NMD systems. In summary, homogeneous nimodipine-starch implants were produced and characterized, which can be used for therapeutic purposes in the brain.

Manufacturing and Assessing the New Orally Disintegrating Tablets, Containing Nimodipine-hydroxypropyl-ß-cyclodextrin and Nimodipine-methyl-ß-cyclodextrin Inclusion Complexes.

The aim of the present study was to manufacture new orally disintegrating tablets containing nimodipine-hydroxypropyl-ß-cyclodextrin and nimodipine-methyl-ß-cyclodextrin inclusion complexes. For obtaining a better quality of the manufactured tablets, three methods of the preparation of inclusion complexes, in a 1:1 molar ratio, were used comparatively; namely, a solid-state kneading method and two liquid state coprecipitation and lyophilization techniques. The physical and chemical properties of the obtained inclusion complexes, as well as their physical mixtures, were investigated using Fourier transformed infrared spectroscopy, scanning electron microscopy, X-ray diffraction analyses, and differential scanning calorimetry. The results showed that the lyophilization method can be successfully used for a better complexation. Finally, the formulation and precompression studies for tablets for oral dispersion, containing Nim-HP-ß-CD and Nim-Me-ß-CD inclusion complexes, were successfully assessed.

Enantioselective assay of nimodipine in human plasma using liquid chromatography-tandem mass spectrometry.

Nimodipine is a dihydropyridine calcium channel blocker that exhibits higher selectivity toward cerebral blood vessels compared with other members of the same class. It has been shown to improve outcomes and prevent delayed cerebral ischemia in the setting of aneurysmal subarachnoid hemorrhage, a life-threatening brain bleed. Nimodipine is a chiral compound and it is marketed as a racemic mixture of (+)-R and (-)-S enantiomers. (-)-S-Nimodipine is approximately twice as potent a vasorelaxant as the racemic mixture and is more rapidly eliminated than the (+)-R counterpart following oral dosing. Few analytical procedures have been reported to determine nimodipine enantiomers in biological samples; however, the reported methods were time-consuming, involved multistep extraction procedures and required large sample volumes. Herein, we present an LC-MS/MS method for quantifying nimodipine enantiomers in human plasma using a small sample volume (0.3 ml) and a single liquid-liquid extraction step. The peak area ratios were linear over the tested concentration ranges (1.5-75 ng/ml) with r2 > 0.99. The intraday CV and percentage error were within ±14% while the interday values were within ±13%, making this analytical method feasible for research purposes and pharmacokinetic studies.

Design, Synthesis and Biological Evaluation of New Antioxidant and Neuroprotective Multitarget Directed Ligands Able to Block Calcium Channels.

We report herein the design, synthesis and biological evaluation of new antioxidant and neuroprotective multitarget directed ligands (MTDLs) able to block Ca2+ channels. New dialkyl 2,6-dimethyl-4-(4-(prop-2-yn-1-yloxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate MTDLs 3a-t, resulting from the juxtaposition of nimodipine, a Ca2+ channel antagonist, and rasagiline, a known MAO inhibitor, have been obtained from appropriate and commercially available precursors using a Hantzsch reaction. Pertinent biological analysis has prompted us to identify the MTDL 3,5-dimethyl-2,6-dimethyl-4-[4-(prop-2-yn-1-yloxy)phenyl]-1,4-dihydro- pyridine- 3,5-dicarboxylate (3a), as an attractive antioxidant (1.75 TE), Ca2+ channel antagonist (46.95% at 10 µM), showing significant neuroprotection (38%) against H2O2 at 10 µM, being considered thus a hit-compound for further investigation in our search for anti-Alzheimer's disease agents.

Co-Stabilization of Amorphous Pharmaceuticals-The Case of Nifedipine and Nimodipine.

Currently, a research hotspot in amorphous active pharmaceutical ingredients (APIs) is to understand the key factors that dominate recrystallization and to develop effective methods for stabilizing amorphous forms. Consequently, we investigated the influence of the global molecular mobility and structural properties on the crystallization tendency of three 1,4-dihydropyridine derivatives (nifedipine, nisoldipine, and nimodipine) in their supercooled states using differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS) techniques. The BDS is also employed to monitor the isothermal crystallization kinetics of supercooled nifedipine and nimodipine at T = 333 K under ambient pressure. As a result, we found that nimodipine exhibits much slower crystallization in comparison to nifedipine. However, nimodipine crystallizes much faster when as little as 10 MPa of pressure is exerted on sample. Such compression-induced crystallization of nimodipine as well as the inherent instability of nifedipine can be solved effectively by preparing coamorphous nifedipine/nimodipine combinations. Interestingly, the high physical stability of nifedipine/nimodipine mixtures is achieved despite the fact that the nimodipine acts as a plasticizer.

Maintaining Supersaturation of Nimodipine by PVP with or without the Presence of Sodium Lauryl Sulfate and Sodium Taurocholate.

Amorphous solid dispersion (ASD) is one of the most versatile supersaturating drug delivery systems to improve the dissolution rate and oral bioavailability of poorly water-soluble drugs. PVP based ASD formulation of nimodipine (NMD) has been marketed and effectively used in clinic for nearly 30 years, yet the mechanism by which PVP maintains the supersaturation and subsequently improves the bioavailability of NMD was rarely investigated. In this research, we first studied the molecular interactions between NMD and PVP by solution NMR, using CDCl3 as the solvent, and the drug-polymer Flory-Huggins interaction parameter. No strong specific interaction between PVP and NMD was detected in the nonaqueous state. However, we observed that aqueous supersaturation of NMD could be significantly maintained by PVP, presumably due to the hydrophobic interactions between the hydrophobic moieties of PVP and NMD in aqueous medium. This hypothesis was supported by dynamic light scattering (DLS) and supersaturation experiments in the presence of different surfactants. DLS revealed the formation of NMD/PVP aggregates when NMD was supersaturated, suggesting the formation of hydrophobic interactions between the drug and polymer. The addition of surfactants, sodium lauryl sulfate (SLS) or sodium taurocholate (NaTC), into PVP maintained that NMD supersaturation demonstrated different effects: SLS could only improve NMD supersaturation with concentration above its critical aggregation concentration (CAC) value while not with lower concentration. Nevertheless, NaTC could prolong NMD supersaturation independent of concentration, with lower concentration outperformed higher concentration. We attribute these observations to PVP-surfactant interactions and the formation of PVP/surfactant complexes. In summary, despite the lack of specific interactions in the nonaqueous state, NMD aqueous supersaturation in the presence of PVP was attained by hydrophobic interactions between the hydrophobic moieties of NMD and PVP. This hydrophobic interaction could be disrupted by surfactants, which interact with PVP competitively, thus hindering the capability of PVP to maintain NMD supersaturation. Therefore, caution is needed when evaluating such ASDs in vitro and in vivo when various surfactants are present either in the formulation or in the surrounding medium.

Surface Enrichment and Depletion of the Active Ingredient in Spray Dried Amorphous Solid Dispersions.

PURPOSE: To study the effects of physicochemical properties of drug and polymer, as well as the drug-polymer interactions, on the surface composition of SDDs. METHODS: Ethanol solutions containing a model drug (IMC, NMP or FCZ) and a model polymer (PVPK12, PVPK30 or PVP-VA) were spray dried, and the surface composition of SDDs was analyzed by XPS. The surface tensions of pure components and their solutions were measured using Wilhelmy plate and/or calculated using ACD/Labs. NMR and DLS were used to obtain the diffusion coefficients of IMC, NMP, PVPK12 and PVPK30 in solvents. Flory-Huggins interaction parameters for selected drug-polymer pairs were obtained using a melting point depression method. RESULTS: Significant surface enrichment or depletion of the drug was observed in SDDs depending on the particular drug-polymer combination. With PVP as the dispersion polymer, IMC and NMP were surface enriched; whereas FCZ, a hydrophilic drug, was surface depleted. With increasing PVP molecular weight, the surface drug concentration increased, and the effect was greater in the NMP/PVP and FCZ/PVP systems than in the IMC/PVP system where strong drug-polymer interaction existed. Changing the polymer from PVP to PVP-VA reduced the surface concentration of the drug. CONCLUSIONS: The surface concentration of a SDD can be significantly different from the bulk concentration. The main results of this work are consistent with the notion that the relative surface tensions control surface enrichment or depletion. Besides, the relative diffusion rates of the components and the strength of their interactions may also affect the surface composition of the SDDs.

Nimodipine Ophthalmic Formulations for Management of Glaucoma.

PURPOSE: Preparation and evaluation of topical ophthalmic formulations containing nimodipine-CD complexes prepared using HP-ß-CD, SBE-ß-CD and M-ß-CD for the management of glaucoma. METHODS: Nimodipine-CD complexes were prepared using a freeze-drying method. Two different molar ratios (NMD:CD) were used for each cyclodextrin. The inclusion complexes were characterized using DSC, FTIR, yield (%), drug content and in vitro release characteristics. NMD-CD complexes incorporated into chitosan eye drops and a temperature-triggered in situ gelling system were evaluated for their pH, viscosity and in vitro release characteristics. We determined the intraocular pressure (IOP) lowering effect of NMD-hydroxypropylmethylcellulose (HPMC) eye drops through a single dose response design using C57BL/6J mice. The minimum effective concentration (MEC) of nimodipine was further applied to mice that vary in the parental allele of Cacna1s, the drug target of nimodipine. Cytotoxicity was also evaluated. RESULTS: Our ophthalmic formulations possessed pH and viscosity values that are compatible with the eye. In vitro release of nimodipine was significantly increased from chitosan eye drops containing NMD-CD complexes compared to uncomplexed drug. Administration of nimodipine can lower IOP significantly after a single drop of drug HPMC suspension. The IOP-lowering response of the MEC (0.6%) was significantly influenced by the parental allele of Cacna1s. CONCLUSIONS: Nimodipine can be used as a promising topical drug for management of glaucoma through ocular delivery.

Effect of pore size of three-dimensionally ordered macroporous chitosan-silica matrix on solubility, drug release, and oral bioavailability of loaded-nimodipine.

OBJECTIVE: To explore the effect of the pore size of three-dimensionally ordered macroporous chitosan-silica (3D-CS) matrix on the solubility, drug release, and oral bioavailability of the loaded drug. METHODS: 3D-CS matrices with pore sizes of 180 nm, 470 nm, and 930 nm were prepared. Nimodipine (NMDP) was used as the drug model. The morphology, specific surface area, and chitosan mass ratio of the 3D-CS matrices were characterized before the effect of the pore size on drug crystallinity, solubility, release, and in vivo pharmacokinetics were investigated. RESULTS: With the pore size of 3D-CS matrix decreasing, the drug crystallinity decreased and the aqueous solubility increased. The drug release was synthetically controlled by the pore size and chitosan content of 3D-CS matrix in a pH 6.8 medium, while in a pH 1.2 medium the erosion of the 3D-CS matrix played an important role in the decreased drug release rate. The area under the curve of the drug-loaded 3D-CS matrices with pore sizes of 930 nm, 470 nm, and 180 nm was 7.46-fold, 5.85-fold, and 3.75-fold larger than that of raw NMDP respectively. CONCLUSION: Our findings suggest that the oral bioavailability decreased with a decrease in the pore size of the matrix.

Synthesis and evaluation of mesoporous carbon/lipid bilayer nanocomposites for improved oral delivery of the poorly water-soluble drug, nimodipine.

PURPOSE: A novel mesoporous carbon/lipid bilayer nanocomposite (MCLN) with a core-shell structure was synthesized and characterized as an oral drug delivery system for poorly water-soluble drugs. The objective of this study was to investigate the potential of MCLN-based formulation to modulate the in vitro release and in vivo absorption of a model drug, nimodipine (NIM). METHODS: NIM-loaded MCLN was prepared by a procedure involving a combination of thin-film hydration and lyophilization. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), specific surface area analysis, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were employed to characterize the NIM-loaded MCLN formulation. The effect of MCLN on cell viability was assessed using the MTT assay. In addition, the oral bioavailability of NIM-loaded MCLN in beagle dogs was compared with that of the immediate-release formulation, Nimotop®. RESULTS: Our results demonstrate that the NIM-loaded MCLN formulation exhibited a typical sustained release pattern. The NIM-loaded MCLN formulation achieved a greater degree of absorption and longer lasting plasma drug levels compared with the commercial formulation. The relative bioavailability of NIM for NIM-loaded MCLN was 214%. MCLN exhibited negligible toxicity. CONCLUSION: The data reported herein suggest that the MCLN matrix is a promising carrier for controlling the drug release rate and improving the oral absorption of poorly water-soluble drugs.

Application of chemometric methods to differential scanning calorimeter (DSC) to estimate nimodipine polymorphs from cosolvent system.

The focus of this study was to evaluate the applicability of chemometrics to differential scanning calorimetry data (DSC) to evaluate nimodipine polymorphs. Multivariate calibration models were built using DSC data from known mixtures of the nimodipine modification. The linear baseline correction treatment of data was used to reduce dispersion in thermograms. Principal component analysis of the treated and untreated data explained 96% and 89% of the data variability, respectively. Score and loading plots correlated variability between samples with change in proportion of nimodipine modifications. The R(2) for principal component regression (PCR) and partial lease square regression (PLS) were found to be 0.91 and 0.92. The root mean square of standard error of the treated samples for calibration and validation in PCR and PLS was found to be lower than the untreated sample. These models were applied to samples recrystallized from a cosolvent system, which indicated different proportion of modifications in the mixtures than those obtained by placing samples under different storage conditions. The model was able to predict the nimodipine modifications with known margin of error. Therefore, these models can be used as a quality control tool to expediently determine the nimodipine modification in an unknown mixture.

Neuroprotective and neuroregenerative effects of nimodipine in a model system of neuronal differentiation and neurite outgrowth.

Nimodipine is a Ca2+-channel antagonist mainly used for the management of aneurysmal subarachnoid hemorrhage (aSAH) to prevent cerebral vasospasms. However, it is not clear if the better outcome of nimodipine-treated patients is mainly due to vasodilatation or whether other cellular neuroprotective or neuregenerative effects of nimodipine are involved. We analysed PC12 cells after different stress stimuli with or without nimodipine pretreatment. Cytotoxicity of 200 mM EtOH and osmotic stress (450 mosmol/L) was significantly reduced with nimodipine pretreatment, while nimodipine has no influence on the hypoxia-induced cytotoxicity in PC12 cells. The presence of nimodipine also increased the NGF-induced neurite outgrowth in PC12 cells. However, nimodipine alone was not able to induce neurite outgrowth in PC12 cells. These results support the idea that nimodipine has general neuroprotective or neuregenerative effect beside its role in vasodilatation and is maybe useful also in other clinical applications beside aSAH.

Comparison of Univariate and Multivariate Models of ¹³C SSNMR and XRPD Techniques for Quantification of Nimodipine Polymorphs.

The focus of the present investigation was to explore the use of solid-state nuclear magnetic resonance ((13)C ssNMR) and X-ray powder diffraction (XRPD) for quantification of nimodipine polymorphs (form I and form II) crystallized in a cosolvent formulation. The cosolvent formulation composed of polyethylene glycol 400, glycerin, water, and 2.5% drug, and was stored at 5°C for the drug crystallization. The (13)C ssNMR and XRPD data of the sample matrices containing varying percentages of nimodipine form I and form II were collected. Univariate and multivariate models were developed using the data. Least square method was used for the univariate model generation. Partial least square and principle component regressions were used for the multivariate models development. The univariate models of the (13)C ssNMR were better than the XRPD as indicated by statistical parameters such as correlation coefficient, R (2), root mean square error, and standard error. On the other hand, the XRPD multivariate models were better than the (13)C ssNMR as indicated by precision and accuracy parameters. Similar values were predicted by the univariate and multivariate models for independent samples. In conclusion, the univariate and multivariate models of (13)C ssNMR and XRPD can be used to quantitate nimodipine polymorphs.

Effects of the Preparation Method on the Formation of True Nimodipine SBE-ß-CD/HP-ß-CD Inclusion Complexes and Their Dissolution Rates Enhancement.

The aims of this study were to enhance the solubility and dissolution rate of nimodipine (ND) by preparing the inclusion complexes of ND with sulfobutylether-b-cyclodextrin (SBE-ß-CD) and 2-hydroxypropyl-b-cyclodextrin (HP-ß-CD) and to study the effect of the preparation method on the in vitro dissolution profile in different media (0.1 N HCl pH 1.2, phosphate buffer pH 7.4, and distilled water). Thus, the inclusion complexes were prepared by kneading, coprecipitation, and freeze-drying methods. Phase solubility studies were conducted to characterize the complexes in the liquid state. The inclusion complexes in the solid state were investigated with differential scanning calorimetry (DSC), X-ray diffractometry (X-RD), and Fourier transform infrared spectroscopy (FT-IR). Stable complexes of ND/SBE-ß-CD and ND/HP-ß-CD were formed in distilled water in a 1:1 stoichiometric inclusion complex as indicated by an AL-type diagram. The apparent stability constants (Ks) were 1334.4 and 464.1 M(-1) for ND/SBE-ß-CD and ND/HP-ß-CD, respectively. The water-solubility of ND was significantly increased in an average of 22- and 8-fold for SBE-ß-CD and HP-ß-CD, respectively. DSC results showed the formation of true inclusion complexes between the drug and both SBE-ß-CD and HP-ß-CD prepared by the kneading method. In contrast, crystalline drug was detectable in all other products. The dissolution studies showed that all the products exhibited higher dissolution rate than those of the physical mixtures and ND alone, in all mediums. However, the kneading complexes displayed the maximum dissolution rate in comparison with drug and other complexes, confirming the influence of the preparation method on the physicochemical properties of the products.

The effect of polymerization method in stereo-active block copolymers on the stability of polymeric micelles and their drug release profile.

PURPOSE: To investigate the effect of polymerization method on the stability and drug release properties of polymeric micelles formed using stereo-active block copolymers. METHODS: Diblock copolymers consisting of methoxy poly ethylene oxide (MePEO) and poly(lactide)s (PLA)s of different stereochemistry were synthesized by bulk or solution polymerization. Polymers and micelles were characterized for their chemical structure by (1)H NMR, optical rotation by polarimetry, critical micellar concentration by fluorescence spectroscopy, thermal properties by differential scanning calorimetry, morphology by transmission electron microscopy and size as well as kinetic stability by dynamic light scattering. Release of encapsulated nimodipine from polymeric micelles at different levels of loading was also investigated. RESULTS: Solution polymerization yielded a higher degree of crystallinity for stereo-regular PLA blocks. Consequently, the related polymeric micelles were kinetically more stable than those prepared by bulk polymerization. At high drug loading levels, the release of nimodipine was more rapid from polymeric micelles with crystalline cores. At lower levels of drug loading, drug release was slower and independent of the stereochemistry of the core. CONCLUSIONS: The results underline the effect of polymerization method in defining core crystallinity in stereoregular block copolymer micelles. It also shows the impact of core crystallinity on enhancing micellar stability and drug release.

Physicochemical characterization of nimodipine-polyethylene glycol solid dispersion systems.

This study investigates the solid-solid interactions between nimodipine (NIM) and polyethylene glycol (PEG) of different mean molecular weights (PEG 2000, 4000 and 6000), in solid dispersion systems, applying differential scanning calorimetry (DSC), Fourier-Transform infrared spectroscopy, powder X-ray diffraction (PXRD), hot stage microscopy (HSM) and theoretical modeling by the Flory-Huggins (FH) solution theory. Phase diagrams constructed with the aid of DSC and FH solution theory showed sensitivity on the estimated values of the FH interaction parameter (χ). When χ is considered a constant number (χ = α, α ≠ 0), formation of a eutectic mixture is predicted in the 70-80% w/w PEG concentration region, while when χ was considered as a function of concentration and temperature (χ = f(φ,Τ)), the model predicts the formation of monotectic systems. Construction of more precise phase diagrams by HSM to the aid of Kofler's "contact preparation" method confirmed the monotectic nature of the examined systems. Studies on NIM's re-crystallization process in the solid dispersions revealed a strong dependence of the crystallization rate, as well as the resulting crystal form, on the mean molecular weight and concentration of PEG: NIM crystallization rates decrease as PEG's MW increases, while NIM mod II crystals predominate in dispersions prepared at temperatures above NIM's liquidus and growth of NIM mod I prevailing in PEG-rich samples.

Anti-arrhythmic and hemodynamic effects of oxy nifedipine, oxy nimodipine, oxy nitrendipine and oxy nisoldipine.

Our previous studies have established cardio-protective effects of furnidipine and its active metabolites. We therefore decided to compare the influence of oral and intravenous administration of furnidipine, nifedipine, nitrendipine and nimodipine to examine their effects on hemodynamics and arrhythmias. Since dihydropyridines are oxidatively metabolized in the body and the oxidized metabolites are among the final products, we studied the influence of four oxidized dihydropyridines (oxy nifedipine, oxy nimodipine, oxy nitrendipine and oxy nisoldipine) on the same parameters. In vivo model of ischemia- and reperfusion-induced arrhythmias of rats was used. Dihydropyridines were administered 5 mg/kg orally (24 and 1 h before ischemia) or 5 µg/kg intravenously (10 min before ischemia). 20 mg/kg of the oxidized dihydropyridines was given orally (24 and 1 h before ischemia). The dihydropyridines exhibited significant anti-arrhythmic actions after both forms of administration but their influence on blood pressure was differential and contrasting and depended on route of administration. The oxidized dihydropyridines imparted strong protection against lethal arrhythmias while exerting differential influences on blood pressure with oxy nifedipine and oxy nisoldipine being hypertensive and oxy nitrendipine being most normotensive. The differential effects observed with the dihydropyridines after the two routes of administration lend strength to the hypothesis that their metabolites may have a significant role in mediating the actions of the parent drug. The strong anti-arrhythmic action of the oxidized dihydropyridines along with their differential effect on blood pressure could indicate their potential use as cardio-protective drugs in certain groups of patients.

Characterization of nimodipine amorphous nanopowder prepared by quenching cooling combined with wet milling and spray drying.

Currently, reducing particle size or preparing drugs into amorphous forms are widely used methods to improve the solubility and dissolution rate of insoluble drugs. The purpose of this study was to prepare nimodipine amorphous nanopowder (NMD-NAP) using nimodipine (NMD) as a model drug to increase the solubility and dissolution rate of insoluble drugs by the combined effect of reducing the particle size and preparing the drug into an amorphous form. The NMD-NAP was successfully prepared by quenching cooling combined with wet milling and spray drying. The prepared NMD-NAP was shown to have good redispersibility by particle size analysis. The shapeof NMD-NAP was characterized by SEM and AFM, showing a spherical or spheroidal structure. The results of PLM, DSC, XRD, and FT-IR indicated that the drug existed in an amorphous form. The dissolution study showed that the dissolution rate of NMD in NMD-NAP was improved about 5 times that of pure NMD and 3 times that of nimodipine nanocrystalline (NMD-NC), indicating the combination of nano size and amorphous form produced a synergistic effect that could significantly increase the dissolution rate of NMD. Due to the significantly improved solubility and good industrial feasibility of the prepared NMD-NAP, the preparation of insoluble drugs into amorphous nanopowders is an effective method to improve the solubility of insoluble drugs and has good application prospects.

Nimodipine (NM) tablets with high dissolution containing NM solid dispersions prepared by hot-melt extrusion.

Using a mixture of Eudragit EPO and polyvinylpyrrolidone/vinyl acetate copolymer (PVP/VA) (Kollidon VA64) as carriers, a nimodipine solid dispersion (NM-SD) was prepared by hot-melt extrusion (HME) to achieve high dissolution. The dissolution profiles in 900 mL 0.1 mol/L HCl showed that the drug release of NM-SD reached 90% in 1h. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) were used to characterize the state of NM. The results obtained showed that NM was in an amorphous form in the solid dispersion (SD). NM-SD tablets (NM-T-SD) were compressed by wet granulation and direct compression, respectively. The stability of NM-T-SD was examined during a 2-month storage period (40 degrees C, RH 75%). The results showed that the dissolution of NM-T-SD was slightly reduced after 2 months storage (40 degrees C, RH 75%), which implied that aging occurred to some degree. However, no NM crystals could be observed by PXRD after 2 months storage for NM-T-SD (F11) prepared by direct compression.

A kinetic study of the polymorphic transformation of nimodipine and indomethacin during high shear granulation.

The objective of the present study was to investigate the mechanism, kinetics, and factors affecting the polymorphic transformation of nimodipine (NMD) and indomethacin (IMC) during high shear granulation. Granules containing active pharmaceutical ingredient, microcrystalline cellulose, and low-substituted hydroxypropylcellulose were prepared with ethanolic hydroxypropylcellulose solution, and the effects of independent process variables including impeller speed and granulating temperature were taken into consideration. Two polymorphs of the model drugs and granules were characterized by X-ray powder diffraction analysis and quantitatively determined by differential scanning calorimetry. A theoretical kinetic method of ten kinetic models was applied to analyze the polymorphic transformation of model drugs. The results obtained revealed that both the transformation of modification I to modification II of NMD and the transformation of the α form to the γ form of IMC followed a two-dimensional nuclei growth mechanism. The activation energy of transformation was calculated to be 7.933 and 56.09 kJ·mol(-1) from Arrhenius plot, respectively. Both the granulating temperature and the impeller speed affected the transformation rate of the drugs and, in particular, the high shear stress significantly accelerated the transformation process. By analyzing the growth mechanisms of granules in high-shear mixer, it was concluded that the polymorphic transformation of NMD and IMC took place in accordance with granule growth in a high-shear mixer.