Correlation of Inhibitory Effects of Polymers on Indomethacin Precipitation in Solution and Amorphous Solid Crystallization Based on Molecular Interaction

Purpose

To correlate the polymer’s degree of precipitation inhibition of indomethacin in solution to the amorphous stabilization in solid state.

Methods

Precipitation of indomethacin (IMC) in presence of polymers was continuously monitored by a UV spectrophotometer. Precipitates were characterized by PXRD, IR and SEM. Solid dispersions with different polymer to drug ratios were prepared using solvent evaporation. Crystallization of the solid dispersion was monitored using PXRD. Modulated differential scanning calorimetry (MDSC), IR, Raman and solid state NMR were used to explore the possible interactions between IMC and polymers.

Results

PVP K90, HPMC and Eudragit E100 showed precipitation inhibitory effects in solution whereas Eudragit L100, Eudragit S100 and PEG 8000 showed no effect on IMC precipitation. The rank order of precipitation inhibitory effect on IMC was found to be PVP K90?>?Eudragit E100?>?HPMC. In the solid state, polymers showing precipitation inhibitory effect also exhibited amorphous stabilization of IMC with the same rank order of effectiveness. IR, Raman and solid state NMR studies showed that rank order of crystallization inhibition correlates with strength of molecular interaction between IMC and polymers.

Conclusions

Correlation is observed in the polymers ability to inhibit precipitation in solution and amorphous stabilization in the solid state for IMC and can be explained by the strength of drug polymer interactions.     

Investigation of the release mechanism of a sparingly water-soluble drug from solid dispersions in hydrophilic carriers based on physical state of drug, particle size distribution and drug-polymer interactions.

In the present study the release mechanism of the sparingly water-soluble drug felodipine (FELO) from particulate solid dispersions in PVP or PEG was investigated. FT-IR data indicated that a N-H...O hydrogen bond is formed between FELO and polymers. The drug-polymer interaction was theoretically studied with the density functional theory with the B3LYP exchange correlation function. The interaction energies have been estimated at -31.8 kJ/mol for PVP and -18.8 kJ/mol for PEG. Also, detailed vibrational analysis of the complexes showed that the red shift of the N-H bond stretching in FELO molecule due to H-bonding was higher in the FELO-PVP complex than in the FELO-PEG complex. Both the experimental and theoretical data indicated that a stronger interaction of FELO with PVP than with PEG was developed. The interactions of FELO with the polymer appeared to control the physical state (amorphous or crystalline) and the particle size of FELO in the solid dispersions. In the FELO/PVP dispersions, the drug is found as amorphous nanoparticles whereas in FELO/PEG dispersions the drug is dispersed as crystalline microparticles. The size of drug particles in the dispersion was also influenced by drug proportion, with an increase in drug content of the dispersion resulting in increased drug particle size. The particle size of drug, the proportion of drug in the dispersion and the properties of the polymer (molecular weight) appeared to determine the mechanism of drug release from the solid dispersions, which was drug diffusion (through the polymer layer)-controlled at low drug contents and drug dissolution-controlled at high drug contents. In situ DLS measurements indicate that the large initial particles of FELO/PVP and FELO/PEG solid dispersions with low drug content (10-20 wt%) are very rapidly decreased to smaller particles (including nanoparticles) during dissolution, leading to the observed impressive enhancement of FELO release rate from these dispersions.     

Improved physical stability of amorphous state through acid base interactions

To investigate role of specific interactions in aiding formation and stabilization of amorphous state in ternary and binary dispersions of a weakly acidic drug. Indomethacin (IMC), meglumine (MU), and polyvinyl pyrollidone (PVP) were the model drug, base, and polymer, respectively. Dispersions were prepared using solvent evaporation. Physical mixtures were cryogenically coground. XRPD, PLM, DSC, TGA, and FTIR were used for characterization. MU has a high crystallization tendency and is characterized by a low T(g) (17 degrees C). IMC crystallization was inhibited in ternary dispersion with MU compared to IMC/PVP alone. An amorphous state formed readily even in coground mixtures. Spectroscopic data are indicative of an IMC-MU amorphous salt and supports solid-state proton transfer. IMC-MU salt displays a low T(g) approximately 50 degrees C, but is more physically stable than IMC, which in molecular mixtures with MU, resisted crystallization even when present in stoichiometric excess of base. This is likely due to a disrupted local structure of amorphous IMC due to specific interactions. IMC showed improved physical stability on incorporating MU in polymer, in spite of low T(g) of the base indicating that chemical interactions play a dominant role in physical stabilization. Salt formation could be induced thermally and mechanically.     

Formulation optimization of solid dispersion of mosapride hydrochloride

Mosapride citrate (MSP) is a gastroprokinetic agent that acts as a selective 5-HT₄ agonist and accelerates the gastric emptying, and is used for the treatment of acid reflux, irritable bowel syndrome, and functional dyspepsia. The purpose of this study is to investigate the solid dispersion formulations of MSP with controlled release characteristic using various polymers, elucidate the release mechanism, and characterize the interaction patterns between MSP and polymers. Solid dispersions of MSP with different drug-to-polymer ratios were prepared by a solvent evaporation method and characterized in comparison with the simple physical mixtures. Eudragit RSPO, Eudragit RLPO, hydroxypropylmethylcellulose (HPMC) or Kollidon SR® was used as a controlled-release polymer along with polyvinylpyrrolidone (PVP) as a carrier. Characterization of MSP solid dispersion was performed using thermal analysis (DSC), powder X-ray diffraction (XRD), Fourier transform-infrared (FT-IR) spectroscopy, where the drug was converted from the crystalline state to amorphous state in all polymeric carriers used. In vitro dissolution studies showed that the drug release has been extended up to 24 h by using Eudragit RSPO or HPMC. Moreover, the formulations containing higher polymer content ratio showed better slow-release profile. These results indicate that the solid dispersion formulation containing PVP/Eudragit RSPO or HPMC mixture could serve as a good controlled-release system for MSP.     

Enhanced Release of Indomethacin from PVP/Stearic Acid Microcapsules Prepared Coupling Co-freeze-drying and Ultrasound Assisted Spray-congealing Process

Purpose Fast releasing indomethacin microparticles were prepared encapsulating co-freeze-dried indomethacin/poly(vinylpyrrolidone) particles (IMC/PVP) into molten stearic acid (SA), by means of a ultrasonic spray-congealing technique. Materials and Methods IMC particles were suspended in a PVP aqueous solution and the system was then freeze-dried. A suspension was prepared from the co-freeze dried IMC/PVP powder into molten SA that was then atomized into small droplets using ultrasound. Solidification in air produced microparticles having regular macroscopic morphology and coated by a SA thin external film. At each step the material was examined by electron microscopy (SEM and EDAX), thermal analysis and dissolution tests. Results SEM examination did not reveal a smooth surface, differently from what was observed in the case of pure SA microparticles, obtained by the same method. The external film was found to uniformly protect the internal core of the capsules: EDAX spectra demonstrated the absence of the IMC identifying Cl peak on the surface, when the spectra were carried out at low energy of the electron beam. HPLC analysis verified that the drug was uniformly distributed inside the final microparticles at all the size fractions considered. Thermal microscopy confirmed the presence of IMC crystals, after the fusion of the external SA coat. Conclusions The behavior of microparticles to dissolution at pH 7.4 was superior to that of pure drug, reaching 70% of the drug released, after 20 min. Finally the system examined is stable towards aging: no difference in the dissolution behavior could be detected for the final microparticles after 8 months at 25°C.     

Physicochemical characterization and dissolution study of solid dispersions of Lovastatin with polyethylene glycol 4000 and polyvinylpyrrolidone K30

Solid dispersions in water-soluble carriers have attracted considerable interest as a means of improving the dissolution rate, and hence possibly bioavailability, of a range of hydrophobic drugs. The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug, Lovastatin, by a solid dispersion technique. Solid dispersions were prepared by using polyethylene glycol 4000 (PEG 4000) and polyvinylpyrrolidone K30 (PVP K30) in different drug-to-carrier ratios. Dispersions with PEG 4000 were prepared by fusion-cooling and solvent evaporation, whereas dispersions containing PVP K30 were prepared by solvent evaporation technique. These new formulations were characterized in the liquid state by phase solubility studies and in the solid state by differential scanning calorimetry, X-ray powder diffraction, and FT-IR spectroscopy. The aqueous solubility of Lovastatin was favored by the presence of both polymers. The negative values of the Gibbs free energy and enthalpy of transfer explained the spontaneous transfer from pure water to the aqueous polymer environment. Solid-state characterization indicated Lovastatin was present as amorphous material and entrapped in polymer matrix. In contrast to the very slow dissolution rate of pure Lovastatin, the dispersion of the drug in the polymers considerably enhanced the dissolution rate. This can be attributed to improved wettability and dispersibility, as well as decrease of the crystalline and increase of the amorphous fraction of the drug. Solid dispersion prepared with PVP showed the highest improvement in wettability and dissolution rate of Lovastatin. Even physical mixture of Lovastatin prepared with both polymers also showed better dissolution profile than that of pure Lovastatin. Tablets containing solid dispersion prepared with PEG and PVP showed significant improvement in the release profile Lovastatin compared with tablets containing Lovastatin without PEG or PVP.     

Physicochemical Characterization and Dissolution Study of Solid Dispersions of Lovastatin with Polyethylene Glycol 4000 and Polyvinylpyrrolidone K30

Solid dispersions in water-soluble carriers have attracted considerable interest as a means of improving the dissolution rate, and hence possibly bioavailability, of a range of hydrophobic drugs. The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug, Lovastatin, by a solid dispersion technique. Solid dispersions were prepared by using polyethylene glycol 4000 (PEG 4000) and polyvinylpyrrolidone K30 (PVP K30) in different drug-to‐carrier ratios. Dispersions with PEG 4000 were prepared by fusion-cooling and solvent evaporation, whereas dispersions containing PVP K30 were prepared by solvent evaporation technique. These new formulations were characterized in the liquid state by phase solubility studies and in the solid state by differential scanning calorimetry, X-ray powder diffraction, and FT-IR spectroscopy. The aqueous solubility of Lovastatin was favored by the presence of both polymers. The negative values of the Gibbs free energy and enthalpy of transfer explained the spontaneous transfer from pure water to the aqueous polymer environment. Solid-state characterization indicated Lovastatin was present as amorphous material and entrapped in polymer matrix. In contrast to the very slow dissolution rate of pure Lovastatin, the dispersion of the drug in the polymers considerably enhanced the dissolution rate. This can be attributed to improved wettability and dispersibility, as well as decrease of the crystalline and increase of the amorphous fraction of the drug. Solid dispersion prepared with PVP showed the highest improvement in wettability and dissolution rate of Lovastatin. Even physical mixture of Lovastatin prepared with both polymers also showed better dissolution profile than that of pure Lovastatin. Tablets containing solid dispersion prepared with PEG and PVP showed significant improvement in the release profile of Lovastatin compared with tablets containing Lovastatin without PEG or PVP.     

吲哚美辛固体分散体的制备和理化性质的研究

目的:研究吲哚美辛(IMC)固体分散体的理化性质,提高IMC的溶出速度。方法:用溶剂法制备固体分散体,用粉末X射线衍射研究原型药物、载体、固体分散体(比例1∶1～1∶5)的物态性质,考察药物在分散体中溶出行为的改变。结果:制得的固体分散体大大提高了IMC的溶出速度,5min内溶出了将近100%的药物。结论:通过溶剂法,成功制备了IMC的固体分散体,药物在分散体中以无定型的状态存在,在溶出介质中药物能够迅速溶出。     

Nanoparticle formation and growth during in vitro dissolution of ketoconazole solid dispersion

The aim of this study is to examine the physical mechanisms during the dissolution of a solid dispersion, so as to provide further understanding behind the enhanced dissolution properties. X-ray amorphous solid dispersions of ketoconazole (KC), a poorly aqueous soluble drug, were prepared by melt extrusion with polyvinlypyrrolidone 17 (PVP 17) and PVP-vinyl acetate (PVP-VA64) copolymer. Prior to dissolution, Raman mapping showed a fully homogeneous spatial distribution of KC in polymer and possible drug dispersion at molecular level, whereas Fourier transform infrared spectroscopy revealed no drug-polymer chemical interaction. During in vitro dissolution test, a burst release followed by a gradual decline in dissolution could be explained by the release of KC in molecular form followed by formation of drug nanoparticles and their subsequent growth to micron size range as shown by dynamic light scattering analysis. Observations using transmission electron microscopy and cryogenic scanning electron microscopy provided support to the suggested mechanisms. The results suggested that the release of KC from the solid dispersions was carrier controlled initially, and PVP 17 PF is more efficient in inhibiting particle growth as compared with PVP-VA64. The particle growth inhibition during dissolution may be an important consideration to achieve the full benefits of dissolution enhancement of solid dispersions.     

Preparation and in vivo evaluation of immediate-release pellet containing celecoxib solid dispersion

The aim of this study was to make use of small size of immediate-release (IR) pellet and amorphous state of solid dispersion to increase solubility of celecoxib (CLX), a drug in BCS class II. Primary, binary and ternary solid dispersions were developed to choose the final components for solid dispersion. A ternary novel solid dispersion was prepared by incorporation of one aqueous soluble polymer (povidone k17; PVP 17PF), Methacrylate copolymer-based gastric soluble polymer (Eudragit^? EPO) and one pH modulator (MgO). This combination was effective to increase solubility in pH 1.2 up to 25?C30?%. The mechanism of solubility enhancement was proven by DSC, PRXD, and FT-IR. Accordingly, hydrogen bonding or electrostatic interaction of CLX with PVP/Eudragit^? EPO was the main cause to form the amorphous state of CLX within polymer cluster which increasing solubility of drug. Besides, MgO played an important role to change microenviroment for solid dispersion. Pellets containing this solid dispersion were prepared by extrusion and spheronization technique. Effect of four kinds of additive (calcium hydrogen phosphate dihydrate, NaHCO₃, crospovidone, and sodium dodecyl sulfate) on dissolution of CLX from IR pellet was also determined. Because of highest dissolution rate, formulation using sodium dodecyl sulfate was used for pharmacokinetics study. Solid dispersion-IR pellet formulation presented bioequivalence and lower variability in comparison with reference product.     

Design of a drug delivery system with bimodal pH dependent release of a poorly soluble drug

A delivery system which provides bimodal pH dependent release of poorly water soluble carvedilol in gastric and intestinal environment was designed. Preparation of solid dispersion with porous silica ensured a significantly higher dissolution rate of carvedilol in acidic and alkaline media in comparison to pure drug, while granulation of that solid dispersion with enteric polymer dispersion resulted in diminished immediate release in acidic media and fast release of the remaining drug in alkaline media. The ratio in quantities of first vs. second release was controlled with amount of enteric polymer dispersion used for granulation process. Desired 25 mg release of carvedilol at pH values 1.2 and 6.8 was achieved when 1.80 g of polymer per 1.0 g of solid dispersion (drug to silica ratio= 0.25 g : 2.0 g) was used.     

Water vapor absorption into amorphous hydrophobic drug/poly(vinylpyrrolidone) dispersions

Water vapor absorption isotherms were measured for three amorphous hydrophobic drug/poly(vinylpyrrolidone) (PVP) dispersions in the concentration range 10-90% w/w PVP. Experimental isotherms were compared to predicted isotherms calculated using each individual component isotherm multiplied by its weight fraction. Indomethacin (IMC)/PVP, ursodeoxycholic acid (UDCA)/PVP and indapamide (IDP)/PVP amorphous dispersions all exhibited experimental isotherms reduced relative to predicted isotherms indicating that dispersion formation altered the water vapor absorption properties of the individual components. For all three drug/PVP systems, deviation from predicted water uptake was greatest close to the 1:1 drug:PVP monomer composition, indicating that intermolecular interaction in amorphous dispersions affects the water uptake properties of the individual components. Using dry glass transition temperature (T(g)) data, the extent of drug/PVP interaction was shown to be greatest in the IDP/PVP system, which could explain why the largest reduction in water vapor absorption was found in this system. The plasticizing effect of absorbed water varied according to dry dispersion PVP content in all systems and the resulting nonideal changes in free volume, calculated using the Vrentas model, were greatest close to the 1:1 drug:PVP monomer composition. A three-component Flory-Huggins model successfully predicted isotherms for IMC/PVP compositions from 60 to 90% w/w PVP and identified an IMC-PVP interaction parameter chi in the range 1.27-1.49, values that suggest poor homogeneity of mixing in the dry system. These data indicate that amorphous dispersion formation causes both chemical and physical changes in the individual amorphous components that can have a significant effect on their water vapor absorption properties.     

Molecular Dynamics Simulation of Amorphous Indomethacin-Poly(Vinylpyrrolidone) Glasses: Solubility and Hydrogen Bonding Interactions

Amorphous drug dispersions are frequently employed to enhance solubility and dissolution of poorly water-soluble drugs and thereby increase their oral bioavailability. Because these systems are metastable, phase separation of the amorphous components and subsequent drug crystallization may occur during storage. Computational methods to determine the likelihood of these events would be very valuable, if their reliability could be validated. This study investigates amorphous systems of indomethacin (IMC) in poly(vinylpyrrolidone) (PVP) and their molecular interactions by means of molecular dynamics (MD) simulations. IMC and PVP molecules were constructed using X-ray diffraction data, and force-field parameters were assigned by analogy with similar groups in Amber-ff03. Five assemblies varying in PVP and IMC composition were equilibrated in their molten states then cooled at a rate of 0.03 K/ps to generate amorphous glasses. Prolonged aging dynamic runs (100 ns) at 298 K and 1 bar were then carried out, from which solubility parameters, the Flory-Huggins interaction parameter, and associated hydrogen bonding properties were obtained. Calculated glass transition temperature (T_g) values were higher than experimental results because of the faster cooling rates in MD simulations. Molecular mobility as characterized by atomic fluctuations was substantially reduced below the T_g with IMC–PVP systems exhibiting lower mobilities than that found in amorphous IMC, consistent with the antiplasticizing effect of PVP. The number of IMC–IMC hydrogen bonds (HBs) formed per IMC molecule was substantially lower in IMC–PVP mixtures, particularly the fractions of IMC molecules involved in two or three HBs with other IMC molecules that may be potential precursors for crystal growth. The loss of HBs between IMC molecules in the presence of PVP was largely compensated for by the formation of IMC–PVP HBs. The difference (6.5 MPa^1/2) between the solubility parameters in amorphous IMC (25.5 MPa^1/2) and PVP (19.0 MPa^1/2) suggests a small, positive free energy of mixing, although it is close to the criterion for miscibility (< 7 MPa^1/2). In contrast to the solubility-parameter method, the calculated Flory-Huggins interaction parameter (? 0.61 ± 0.25), which takes into account the IMC–PVP interaction energy, predicts complete miscibility at all PVP compositions, in agreement with experimental observations. These results from MD simulations were combined with experimental values for the crystalline γ-polymorph of IMC and amorphous IMC to estimate the solubility of IMC in amorphous PVP dispersions and the theoretical enhancement in the aqueous solubility of IMC molecularly dispersed in PVP at various volume fractions. © 2012Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:876–891, 2013     

Formation and characterization of porous indomethacin-PVP coprecipitates prepared using solvent-free supercritical fluid processing

Supercritical carbon dioxide (sc-CO2) was used to prepare coprecipitates of indomethacin (IM) and poly(vinylpyrrolidone) (PVP) with the aim to improve the dissolution rate of IM. The coprecipitates of IM and PVP at various proportions were prepared using a stirred batch reactor containing sc-CO2 as a gas saturated solution (i.e., the compressible CO2 is dissolved in the molten compound). Temperatures between 40 and 90 degrees C and pressure of 150 or 200 bar were employed. The coprecipitates prepared at 75 degrees C and 150 bar were characterized using differential scanning calorimetry (DSC), powder X-ray diffraction (PXD), scanning electron microscopy (SEM), and dissolution testing. The results suggested that IM was totally amorphous at PVP weight fraction of 0.80 and above (indeed, as a molecular composite in which the drug molecules interact with the polymer backbone). As the PVP weight fraction decreased, IM displayed an increasing amount of crystalline material. The SEM photographs of coprecipitates showed a foamed and porous structure. The dissolution rate of IM was increased by incorporation of PVP. IM and PVP at various weight fractions exhibited comparatively higher dissolution rates than that of crystalline IM alone. The sc-CO2 based process produced a solvent free, completely amorphous porous IM solid dispersion with a rapid dissolution rate.     

Ivermectin-loaded microparticles for parenteral sustained release: in vitro characterization and effect of some formulation variables

Ivermectin (IVM) is a BCS II drug with potent antiparasitic activity in veterinary applications. In this study, poly(lactide-co-glycolide) (PLGA) and poly(DL-lactide) (PLA) Ivermectin-loaded microparticles were prepared by the simple emulsion (O/W) solvent evaporation method in order to obtain sustained release formulations for parenteral applications. The effects of polymer end-groups (ester or free acid) and the addition of the hydrophilic polyvinylpyrrolidone polymer (PVP) in in vitro drug release profiles were also studied. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analysis showed that IVM was present in an amorphous state or as a molecular dispersion within the polymers or theirs mixtures with PVP and that a PVP-drug complex was formed. Drug entrapment efficiency in the microparticles (>90%) was independent of the polymer composition, the end groups and the presence of PVP. However, microscopic (SEM) observations showed that the addition of PVP led to more porous microparticles accompanied by the increased rates of drug release.     

Application of quartz crystal microbalance to study the impact of pH and ionic strength on protein-silicone oil interactions

The effect of adding a third polymer to immiscible binary solid dispersions was investigated. The model actives griseofulvin (GF), progesterone (PG) and phenindione (PD) were selected because they exemplify a key property of many poorly soluble molecules of having at least one hydrogen bonding acceptor moiety while not having any hydrogen bond donating moieties. Ternary solid dispersions of the drug, PVP (polyvinylpyrrolidone) (proton acceptor) and PHPMA (poly[2-hydroxypropyl methacrylate]) (proton acceptor and donor) were prepared by spray drying. Stability results showed that binary solid dispersions (API and PVP) of GF and PVP crystallized quickly while the amorphous form was not possible to prepare for PG and PD. The amorphous form was prolonged upon the incorporation of PHPMA in the solid dispersion (API, PHPMA and PVP). Based on measuring the melting points, the energy of mixing the drug with the polymer was calculated using the Flory-Huggins theory. The results showed that GF had the lowest free energy followed by PG and finally PD which agreed well with the stability results. These results suggest that the addition of a third polymer to immiscible binary solid dispersions can significantly improve the stability of the amorphous form.     

The characterization and dissolution performances of spray dried solid dispersion of ketoprofen in hydrophilic carriers

Solid dispersion is one of the most promising strategies to improve oral bioavailability of poorly soluble API. However, there are inconsistent dissolution performances of solid dispersion reported which entails further investigation. In this study, solid dispersions of ketoprofen in three hydrophilic carriers, i.e. PVP K30, PVPVA 6:4 and PVA were prepared and characterized. Physical characterization of the physical mixture of ketoprofen and carriers shows certain extent of amorphization of the API. This result is coinciding to evaluation of drug–polymer interaction using ATR-FTIR whereby higher amorphization was seen in samples with higher drug–polymer interaction. XRPD scanning confirms that fully amorphous solid dispersion was obtained for SD KTP PVP K30 and PVPVA system whereas partially crystalline system was obtained for SD KTP PVA. Interestingly, dissolution profiles of the solid dispersion had shown that degree of amorphization of KTP was not directly proportional to the dissolution rate enhancement of the solid dispersion system. Thus, it is concluded that complete amorphization does not guarantee dissolution enhancement of an amorphous solid dispersion system.     

Inhibition of a solid phase reaction among excipients that accelerates drug release from a solid dispersion with aging

Hydrophobic drug substances can be formulated as a solid dispersion or solution using macromolecular matrices with high glass transition temperatures to attain satisfactory dissolution. However, very few marketed products have previously relied on solid dispersion technology due to physical and chemical instability problems, and processing difficulties. In the present study, a modified release product of a therapeutic drug for hypertension, Barnidipine hydrochloride, was developed. The drug product consisted of solid dispersion based on a matrix of carboxymethylethylcellulose (CMEC), which was produced using the spray-coating method. An enteric coat layer was sprayed on the surface of the solid dispersion to control drug release. Interestingly, the release rate accelerated as the drug product aged, while there were no indications of deceleration of the release rate which was due to crystallization of the drug substance. To prevent changes in the dissolution kinetics during storage periods, a variety of processing conditions were tried. It was found that not only use of non-aqueous solvents but also a reduction in coating temperatures consistently resulted in stable solid dispersions. The molecular bases of dissolution of the drug substance from those matrices were investigated. The molecular weight of CMEC was found to be a dominant factor that determined dissolution kinetics, which followed zero-order release, suggesting an involvement of an osmotic pumping mechanism. While dissolution was faster using a higher molecular weight CMEC, the molecular weight of CMEC in the drug product slowly increased with aging (solid phase reaction) depending on the processing conditions, causing the time-induced elevation of dissolution. While no crystalline components were found in the solid dispersion, the amorphous structure maintained a degree of non-equilibrium by nature. Plasticization by water in the coating solution relaxed the amorphous system and facilitated phase separation of the drug substance and CMEC upon production. The solid phase reaction advanced differentially in the solid dispersion depending on the degree of phase separation set initially. The use of non-aqueous solvents and/or a decrease in the coating temperatures inhibited the occurrence of phase separation upon production, thereby preventing the formation of CMEC-rich phases where the solid phase reaction occurred during storage.     

Bimodal Release of Olanzapine from Lipid Microspheres

Olanzapine was formulated as 10% (w/w) mixture with cutina® to which stearic acid was added, ranging from 10% to 90% (w/w) of the total mass to control the drug release. The molten mixtures were processed by ultrasound-assisted spray-congealing technique, obtaining solid microspheres. The drug is stable under these conditions and only a partial miscibility in the solid state was observed by DSC between the two fatty materials with two separated melting endotherms in the thermograms: this can be due to the presence of two phases inside the solid dispersion. Olanzapine is distributed into the two phases according to its partition coefficient: two phases make the system less suitable to crystallization of the drug; the loading of the drug could reach saturation with difficulty and the rate of the olanzapine release is differentiated, since the drug is released from two different carriers. Dissolution profiles suggest occurrence of a bimodal release, where each portion of the release profile is linear and the slope increases with a higher content of stearic acid in the carrier mixture, that behaves as a release promoter. Tests were also carried out with palmitic and lauric acids for comparison and also for systems in the absence of ultrasound.     

Development of spray-dried co-precipitate of amorphous celecoxib containing storage and compression stabilizers

The purpose of this study was to obtain an amorphous system with minimum unit operations that will prevent recrystallization of amorphous drugs since preparation, during processing (compression) and further storage. Amorphous celecoxib, solid dispersion (SD) of celecoxib with polyvinyl pyrrollidone (PVP) and co-precipitate with PVP and carrageenan (CAR) in different ratios were prepared by the spray drying technique and compressed into tablets. Saturation solubility and dissolution studies were performed to differentiate performance after processing. Differential scanning calorimetry and X-ray powder difraction revealed the amorphous form of celecoxib, whereas infrared spectroscopy revealed hydrogen bonding between celecoxib and PVP. The dissolution profile of the solid dispersion and co-precipitate improved compared to celecoxib and amorphous celecoxib. Amorphous celecoxib was not stable on storage whereas the solid dispersion and co-precipitate powders were stable for 3 months. Tablets of the solid dispersion of celecoxib with PVP and physical mixture with PVP and carrageenan showed better resistance to recrystallization than amorphous celecoxib during compression but recrystallized on storage. However, tablets of co-precipitate with PVP and carageenan showed no evidence of crystallinity during stability studies with comparable dissolution profiles. This extraordinary stability of spray-dried co-precipitate tablets may be attributed to the cushioning action provided by the viscoelastic polymer CAR and hydrogen bonding interaction between celecoxib and PVP. The present study demonstrates the synergistic effect of combining two types of stabilizers, PVP and CAR, on the stability of amorphous drug during compression and storage as compared to their effect when used alone.