Dissolution Rate Of Carbamazepine Research Articles

Dissolution improvement of binary solid dispersions of Carbamazepine using Poly (2-ethyl-2-oxazoline) as the hydrophilic carrier.

Theaim of this study was to design and evaluate the properties of soliddispersions of carbamazepine (CBZ) using poly (2-ethyl-2-oxazoline) (POX) asthe hydrophilic carrier. These binary solid dispersions were prepared at varyingdrug loadings using the solvent evaporation method. The samples were evaluatedfor their in vitro dissolution, and solid-state properties. There was over 350%increase in dissolution rate of CBZ in samples containing at least 50% POX.This study concludes that POX is an effective hydrophilic carrier for poorlysoluble drugs in solid dispersions. 

Hard Gelatin Capsules Containing Hot Melt Extruded Solid Crystal Suspension of Carbamazepine for improving dissolution: Preparation and In vitro Evaluation.

Aqueous solubility is one of the key parameters for achieving the desired drug concentration in systemic circulation for better therapeutic outcomes. Carbamazepine (CBZ) is practically insoluble in water, is a BCS class II drug, and exhibits dissolution-dependent oral bioavailability. This study explored a novel application of hot-melt extrusion in the manufacture and development of a thermodynamically stable solid crystal suspension (SCS) to improve the solubility and dissolution rate of CBZ. The SCSs were prepared using sugar alcohols, such as mannitol or xylitol, as crystalline carriers. The drug-sugar blend was processed by hot melt extrusion up to 40 % (w/w) drug loading. The extruded SCS was evaluated for drug content, saturation solubility, differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy, powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), in vitro release, and stability studies. The physicochemical characterization revealed the highly crystalline existence of pure drug, pure carriers, and extruded SCS. FTIR analysis did not reveal any physical or chemical incompatibilities between the drug and sugar alcohols and showed a homogeneous CBZ distribution within respective crystalline carriers. The SEM micrographs of the solidified SCS revealed the presence of approximately 100 μm crystalline agglomerates. In vitro dissolution and solubility studies showed that the CBZ dissolution rate and solubility were improved significantly from both crystalline carriers for all tested drug loads. The SCSs showed no significant changes in drug content, in vitro release profiles, and thermal characteristics over 3 months of storage at accelerated stability conditions (40±2°C/75±5% RH). As a result, it can be inferred that the SCS strategy can be employed as a contemporary alternative technique to improve the dissolution rate of BCS class II drugs via HME technology.

Characterization of Recrystallized Carbamazepine Using Acetone as Solvent

Carbamazepine is used as a first line drug in seizure treatment. It is classified as BCS class II according to the Biopharmaceutical classification system which means that carbamazepine has high membrane permeability and low water solubility. This makes dissolution the rate limiting process in carbamazepine absorption. Thus crystallization of carbamazepine using the solvent acetone was chosen to increase dissolution rates and improve the bioavailability of carbamazepine. This study therefore aims to compare the characteristics and dissolution rate of carbamazepine recrystallized with acetone using two methods; rapid cooling and solvent evaporation. Characterization of carbamazepine crystals was carried out using Differential Thermal Analysis (DTA), Fourier Transform Infrared (FTIR) Spectroscopy, X-Ray Diffractometry (XRD) and Scanning Electron Microscopy (SEM) while dissolution test was carried out using Type I Dissolution Apparatus operated at 100 rpm and in 900 mL of CO2-free water medium at a temperature of 37 ± 0.5 ◦C. Sampling was carried out at 5, 10, 15, 20, 30, 45, and 60 minutes. The results showed that the melting point, infrared absorption and crystallinity of the acetone recrystallized carbamazepine did not show significant changes compared with the initial carbamazepine compound. The morphology of the recrystallized carbamazepine crystals using the two methods produced a polycrystalline structure which influenced the rate of dissolution. The dissolution rate of acetone recrystallized carbamazepine significantly increased the dissolution of carbamazepine, with a faster dissolution rate for carbamazepine recrystallized using rapid cooling method than the solvent evaporation method or the initial carbamazepine compound.

Solubility and Dissolution Improvement of Carbamazepine by Various Methods

This work was aimed to improve solubility and dissolution rate of carbamazepine (CBZ), an antiepileptic, BCS class II drug by using different solubility enhancement techniques. Self-nanoemulsifying drug delivery system (SNEDDS) and solid dispersions of CBZ was attempted by spontaneous emulsification method and fusion method, respectively. The solubility studies of pure CBZ was performed in different oils, surfactants and co-surfactants. Very small amount of CBZ (20 mg) could be incorporated in SNEDDS, however the solid dispersion of CBZ using Soluplus® was successfully prepared with the required dose. The solid dispersion was characterized and evaluated for saturation solubility, in vitro dissolution studies, solid state characterization such as fourier transform infrared spectroscopy (FTIR) and powder X-ray diffraction studies (XRD). Based on the results, it can be concluded that the due to increased solubility and the dissolution, the bioavailability of CBZ could be improved by preparing solid dispersion

Development of ternary solid dispersions with hydrophilic polymer and surface adsorbent for improving dissolution rate of carbamazepine

In this study solid dispersions of carbamazepine in the hydrophilic Kollidon® VA64 polymer, adsorbed onto Neusilin® UFL2 adsorption carrier have been employed to improve carbamazepine dissolution rate. In order to evaluate effects of changing in the proportions of all solid dispersion components on carbamazepine dissolution rate, D-optimal mixture experimental design was used in the formulation development. From all prepared solid dispersion formulations, significantly faster carbamazepine dissolution was observed compared to pure drug. Ternary solid dispersions containing carbamazepine, Kollidon® VA64 and Neusilin® UFL2 showed superior dissolution performances over binary ones, containing only carbamazepine and Neusilin® UFL2. Proportion of Kollidon® VA64 showed the most profound effect on the amount of carbamazepine dissolved after 10 and 30 min, whereby these parameters increase upon increasing in Kollidon® VA64 concentrations up to the middle values in the studied range of Kollidon® VA64 concentrations. Physicochemical characterization of the selected samples using differential scanning calorimetry, FT-IR spectroscopy, powder X-ray diffraction and polarizing light microscopy showed polymorphic transition of carbamazepine from more thermodynamically stable monoclinic form (form III) to less thermodynamically stable triclinic form (form I) in the case of ternary, but not of binary solid dispersion formulations. This polymorphic transition can be one of the factors responsible for improving of carbamazepine dissolution rate from studied solid dispersions. Ternary solid dispersions prepared with Kollidon® VA64 hydrophilic polymer and Neusilin® UFL2 adsorption carrier resulted in significantly improvement of carbamazepine dissolution rate, but formation of metastable polymorphic form of carbamazepine requires particular care to be taken in ensuring product long term stability.

Solid dispersions with carbamazepine: Optimization of formulation, characterization and examination of long-term stability

Solid dispersions are defined as dispersions of one or more active pharmaceutical ingredients in inert solid-state carriers. They are made with the aim to increase solubility and the dissolution rate of low solubility active pharmaceutical ingredients, with the subsequent increase in their bioavailability. The aim of this study was the development and optimization of solid dispersion formulations with carbamazepine, using D-optimal experimental design, in order to increase the dissolution rate of the selected model drug. By using the method of experimental mixture design, solid dispersions were formulated by varying the ratio of carbamazepine (30-50 %), Gelucire? 44/14 (20-40 %) and Soluplus? polymer (30-50 %) (input parameters). Sixteen formulations were made and used for in vitro testing of the carbamazepine dissolution rate. The observed output parameters were the percentages of carbamazepine released after 10, 20, 30, 45, and 60 minutes. After the data analysis, three test formulations were chosen from different parts of the optimization area. They were prepared and the carbamazepine dissolution rate was determined, followed by stability assessment for 24 months under ambient conditions (25?C, 40 % RH). The highest dissolution rate of carbamazepine from solid dispersions (more than 80 % in 30 minutes) was achieved at the carbamazepine mass fraction of about 40 %, Soluplus? of about 45 % and Gelucire? 44/14 of about 25 %. Comparing the predicted and the experimental obtained release rate profiles of carbamazepine from the three prepared optimized formulations, a significant compliance of the results was observed (f1<15; f2>50). The application of the PAMPA (Parallel Artificial-Membrane Permeability Assay) test has shown that carbamazepine premeability was maintained and mildly increased in two out of the three tested optimzed solid state formulations. Raman spectroscopy, FT-IR and DSC analyes showed that in the three optimized solid dispersions, after preparation and 24 months of storage, interactions between carbamazepine and the excipients were not present and that carbamazepine remained in the single pharmacologically active crystal polymorph form III. Proper selection of solid dispersion proportions of carbamazepine, Gelucire? 44/14 and Soluplus? may significantly increase the dissolution rate of the active substance, and the method of experimental mixture design can be successfully used for optimization of these formulations.

Adsorption onto Mesoporous Silica Using Supercritical Fluid Technology Improves Dissolution Rate of Carbamazepine-a Poorly Soluble Compound.

The purpose of this research was to design and characterize an immediate-release formulation of carbamazepine (CBZ), a poorly soluble anti-epileptic drug, using a porous silica carrier. Carbon dioxide in its supercritical state (2000psi, 30-35°C) was used as an anti-solvent to precipitate CBZ onto two particle size variants of silica. Adsorption isotherms were used as a pre-formulation strategy to select optimum ratios of silica and CBZ. The obtained drug-silica formulations were characterized by dissolution studies, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). This formulation strategy resulted in a 2.4-fold improvement in dissolution rate when compared to pure drug after 30min of dissolution testing. PXRD and DSC confirmed the amorphous nature of CBZ in the formulations as well as the differences in polymorphic forms of commercial and supercritical fluid-processed CBZ. Additionally, solid-state NMR spectroscopy showed that the spin-lattice relaxation time for bulk drug (without silica) was ∼7.5 times greater than that for silica-confined CBZ, implying that when CBZ was adsorbed onto mesoporous silica, it is structurally disordered and had higher structural mobility, a characteristic of amorphous solids. The mesoporous silica matrix prevented CBZ crystal growth by imposing spatial constraint on CBZ nuclei and hence resulted in faster dissolution compared to bulk solid drug. Adsorption onto mesoporous silica using supercritical fluid technology may be used as a novel formulation strategy for amorphization of poorly soluble compounds, in turn improving their dissolution rate.

Evaluation of the effect of some additives on the efficiency of binder liquid in wet agglomeration of crystals

Objective: Wet agglomeration is a process wherein dispersed particles are held together in an aggregated form by the presence of a small quantity of solvent which acts as binder liquid. In this work, the efficiency of binder liquid was tested in the presence of various additives.Methods: Solid state of carbamazepine (CBZ) agglomerates was characterized by DSC and FT-IR. The obtained agglomerates were also investigated in terms of yield, size distribution, friability, and drug release.Results: CBZ agglomerates formed only in the presence of talc, span, and croscarmellose sodium (CCS), whereas ethyl cellulose and eudragit RS100 failed to make CBZ agglomerates. The presence of talc decreased the agglomerate size and produced CBZ agglomerates with a poor strength. However, span and CCS led to larger agglomerates with superior strength. In contrast to CCS samples, span and talc altered the dissolution rate of CBZ. FT-IR results showed that there is an interaction between CCS and drug.Conclusion: This study suggests that care must be taken when additives are used to manufacture agglomerates as the type of additives even in low concentrations can have a big impact on the efficiency of the binder liquid in forming agglomerates thereby affecting the quality of agglomerates.

Application of mixture experimental design in formulation and characterization of solid self-nanoemulsifying drug delivery systems containing carbamazepine

One of the problems with orally used drugs is their poor solubility, which can be overcame by creating solid self-nanoemulsifying drug delivery systems (SNEDDS). Aim is choosing appropriate SNEDDS using mixture design and adsorption of SNEDDS on a solid carrier to improve the dissolution rate of carbamazepine. Self-emulsifying drug delivery systems (SEDDS) consisting of oil phase (caprilic-capric triglycerides), a surfactant (Polisorbat 80 and Labrasol? (1:1)) and cosurfactant (Transcutol? HP) are formed by applying mixture design. 16 formulations were formulated, where proportion of lipids, surfactant and cosurfactant were varied (input parameters) in the following ranges: 10-30%, 40-60%, 30-50%, respectively. After dilution of SEDDS with water (90% water), the droplet size and polydispersity index (PdI) of the obtained emulsions (output parameters) were measured using photon correlation spectroscopy. After processing data, appropriate mathematical models that describe the dependence of input and output parameters were selected. The optimized SNEDDS was adsorbed on the carbamazepine and solid carrier physical mixture, containing 20% carbamazepine. Neusilin? UFl2, Neusilin? FL2, Sylysia? 320, diatomite were used as the carriers. The ratio of SNEDDS:carrier varied (1:1, 2:1). Dissolution testing was carried out in the rotation paddles apparatus. Caracterization of solid SNEDDS was performed using the hot stage microscopy (HSM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), infrared spectrophotometry with Fourier transformation (FT-IR), scanning electron microscopy (SEM) and X-ray diffraction (PXRD). Selected SNEDDS consisting of lipids (21.12%), surfactant (42.24%) and cosurfactant (36.64%) had a droplet size 157.02?34.09 nm and PDI 0.184?0.021. Drug release profiles showed that in all formulations dissolution rate increased (the fastest drug release was observed in formulations with Sylysia? 320). It can be concluded that in all formulations carbamazepine is present in the thermodynamically most stable polymorphic form III. Formulation of solid SNEDDS can significantly increase dissolution rate carbamazepine, with conservation of the polymorphic form III CBZ and potentially increased bioavailability.

Influence of Solid Drug Delivery System Formulation on Poorly Water-Soluble Drug Dissolution and Permeability.

The majority of drugs have a low dissolution rate, which is a limiting step for their absorption. In this manuscript, solid dispersions (SD), solid self-microemulsifying drug delivery systems (S-SMEDDS) and solid self-nanoemulsifying drug delivery systems (S-SNEDDS) were evaluated as potential formulation strategies to increase the dissolution rate of carbamazepine. Influence of increased dissolution rate on permeability of carbamazepine was evaluated using PAMPA test. In S-SMEDDS and S-SNEDDS formulations, the ratio of liquid SMEDDS/SNEDDS and solid carrier (Neusilin® UFL2) was varied, and carbamazepine content was constant. In SD formulations, the ratio of carbamazepine and Neusilin® UFL2, was varied. Formulations that showed the best dissolution rate of carbamazepine (SD_1:6, SMEDDS_1:1, SNEDDS_1:6) were mutually compared, characterization of these formulations was performed by DSC, PXRD and FT-IR analyses, and a PAMPA test was done. All formulations have shown a significant increase in dissolution rate compared to pure carbamazepine and immediate-release carbamazepine tablets. Formulation S-SMEDDS_1:1 showed the fastest release rate and permeability of carbamazepine. DSC, PXRD and FT-IR analyses confirmed that in S-SMEDDS and S-SNEDDS carbamazepine remained in polymorph form III, and that it was converted to an amorphous state in SD formulations. All formulations showed increased permeability of carbamazepine, compared to pure carbamazepine.

Influence of hydrophilic polymers on the complexation of carbamazepine with hydroxypropyl-β-cyclodextrin

In this study binary carbamazepine–hydroxypropyl-β-cyclodextrin, as well as ternary carbamazepine–hydroxypropyl-β-cyclodextrin–hydrophilic polymer systems were used to improve dissolution rate of carbamazepine. It has been shown that addition of hydrophilic polymers (Soluplus® and two types of hydroxypropyl methylcellulose–Metolose® 90SH-100 and Metolose® 65SH-1500) significantly increased solubilization capacity of hydroxypropyl-β-cyclodextrin for carbamazepine. Evaluation of carbamazepine–hydroxypropyl-β-cyclodextrin–hydrophilic polymer interactions using molecular modeling techniques showed interactions between carbamazepine, which dissociates from inclusion complexes and hydroxypropyl methylcellulose that can prevent crystallization of dissolved carbamazepine. These results can contribute to better understanding of drug–cyclodextrin–hydrophilic polymer interactions which are still not well understood. After evaluation of carbamazepine solubilization with hydroxypropyl-β-cyclodextrin and hydrophilic polymers, both binary carbamazepine–hydroxypropyl-β-cyclodextrin and ternary carbamazepine–hydroxypropyl-β-cyclodextrin–hydrophilic polymer systems were prepared by spray drying. The results of solid state characterization methods showed amorphous nature of carbamazepine in all spray dried systems, which together with the results of molecular modeling techniques indicates inclusion complex formation. Carbamazepine dissolution rate was significantly improved from spray dried formulations compared to pure drug. Binary carbamazepine–hydroxypropyl-β-cyclodextrin and ternary carbamazepine–hydroxypropyl-β-cyclodextrin–Soluplus® systems exhibited the fastest carbamazepine release, wherein the entire amount of carbamazepine was released during first 5min.

Combined application of mixture experimental design and artificial neural networks in the solid dispersion development

This study for the first time demonstrates combined application of mixture experimental design and artificial neural networks (ANNs) in the solid dispersions (SDs) development. Ternary carbamazepine–Soluplus®–poloxamer 188 SDs were prepared by solvent casting method to improve carbamazepine dissolution rate. The influence of the composition of prepared SDs on carbamazepine dissolution rate was evaluated using d-optimal mixture experimental design and multilayer perceptron ANNs. Physicochemical characterization proved the presence of the most stable carbamazepine polymorph III within the SD matrix. Ternary carbamazepine–Soluplus®–poloxamer 188 SDs significantly improved carbamazepine dissolution rate compared to pure drug. Models developed by ANNs and mixture experimental design well described the relationship between proportions of SD components and percentage of carbamazepine released after 10 (Q10) and 20 (Q20) min, wherein ANN model exhibit better predictability on test data set. Proportions of carbamazepine and poloxamer 188 exhibited the highest influence on carbamazepine release rate. The highest carbamazepine release rate was observed for SDs with the lowest proportions of carbamazepine and the highest proportions of poloxamer 188. ANNs and mixture experimental design can be used as powerful data modeling tools in the systematic development of SDs. Taking into account advantages and disadvantages of both techniques, their combined application should be encouraged.

Effect of solubility enhancers on the release of Carbamazepine from Hydrophilic Polymer based matrix tablet

In the present study, an attempt has been taken to evaluate the effect of sodium lauryl sulphate (SLS) and glyceryl mono stearate (GMS) as solubility enhancers on the release profile of a poorly soluble drug, carbamazepine. Matrix tablets of carbamazepine were prepared by wet granulation technique using hydrophilic polymers (10% of Methocel K15 MCR and 10% of Methocel K100LV CR) as release controlling agents. Varying amounts of SLS and GMS were used in six different formulations to observe the impact on the release rate and mechanism of drug release. The dissolution study of carbamazepine from these extended release matrix tablets was conducted for 24 hours using basket method in 900 ml distilled water as dissolution medium. The data obtained from the dissolution studies were explored and explained with the help of zero order, Higuchi, first order, Korsmeyer- Peppas and Hixson-Crowell equations. It was found that the dissolution rate of carbamazepine with the formulation containing SLS was higher than GMS containing formulation and increased concentration of SLS increasing the release rate. Where there was no SLS or smaller amount of SLS or GMS release rate was decreased. Formulation having equal ratio of SLS and GMS did not show the desire release profile. The drug release mechanism followed mainly super case II transport. These results clearly demonstrated that the dissolution rate, extent and mechanism of carbamazepine release could be changed by optimizing the amount of SLS and GMS in the tablet formulation. DOI: http://dx.doi.org/10.3329/dujps.v13i2.21894 Dhaka Univ. J. Pharm. Sci. 13(2): 167-173, 2014 (December)

Stability-enhanced Hot-melt Extruded Amorphous Solid Dispersions via Combinations of Soluplus® and HPMCAS-HF

The aim of this study was to evaluate a novel combination of Soluplus® and hypromellose acetate succinate (HPMCAS-HF) polymers for solubility enhancement as well as enhanced physicochemical stability of the produced amorphous solid dispersions. This was accomplished by converting the poorly water-soluble crystalline form of carbamazepine into a more soluble amorphous form within the polymeric blends. Carbamazepine (CBZ), a Biopharmaceutics Classification System class II active pharmaceutical ingredient (API) with multiple polymorphs, was utilized as a model drug. Hot-melt extrusion (HME) processing was used to prepare solid dispersions utilizing blends of polymers. Drug loading showed a significant effect on the dissolution rate of CBZ in all of the tested ratios of Soluplus® and HPMCAS-HF. CBZ was completely miscible in the polymeric blends of Soluplus® and HPMCAS-HF up to 40% drug loading. The extrudates were characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and dissolution studies. DSC and XRD data confirmed the formation of amorphous solid dispersions of CBZ in the polymeric blends of Soluplus® and HPMCAS-HF. Drug loading and release of CBZ was increased with Soluplus® (when used as the primary matrix polymer) when formulations contained Soluplus® with 7-21% (w/w) HPMCAS-HF. In addition, this blend of polymers was found to be physically and chemically stable at 40°C, 75% RH over 12 months without any dissolution rate changes.

Application of experimental design in examination of the dissolution rate of carbamazepine from formulations: Characterization of the optimal formulation by DSC, TGA, FT-IR and PXRD analysis

Poor solubility is one of the key reasons for the poor bioavailability of these drugs. This paper displays a formulation of a solid surfactant system with carbamazepine, in order to increase its dissolution rate. Solid state surfactant systems are formed by application of fractal experimental design. Poloxamer 237 and Poloxamer 338 were used as surfactants and Brij? 35 was used as the co-surfactant. The ratios of the excipients and carbamazepine were varied and their effects on the dissolution rate of carbamazepine were examined. Moreover, the effects of the addition of natural (diatomite) and a synthetic adsorbent carrier (Neusiline UFL2) on the dissolution rate of carbamazepine were also tested. The prepared surfactant systems were characterized and the influence of the excipients on possible changes of the polymorphous form of carbamazepine examined by application of analytical techniques (DSC, TGA, FT-IR, PXRD). It was determined that an appropriate selection of the excipient type and ratio could provide a significant increase in the carbamazepine dissolution rate. By application of analytical techniques, it was found that that the employed excipients induce a transition of carbamazepine into the amorphous form and that the selected sample was stable for three months, when kept under ambient conditions.

The use of inorganic salts to improve the dissolution characteristics of tablets containing Soluplus®-based solid dispersions

The dissolution enhancement advantages inherent to amorphous solid dispersions systems are often not fully realized once they are formulated into a solid dosage form. The objective of this study was to investigate the ability of inorganic salts to improve the dissolution rate of carbamazepine (CBZ) from tablets containing a high loading of a Soluplus®-based solid dispersion. Cloud point and viscometric studies were conducted on Soluplus® solutions to understand the effect of temperature, salt type and salt concentration on the aqueous solubility and gelling tendencies of Soluplus®, properties that can significantly impact dissolution performance. Studies indicated that Soluplus® exhibited a cloud point that was strongly dependent on the salt type and salt concentration present in the dissolving medium. The presence of kosmotropic salts dehydrated the polymer, effectively lowering the cloud point and facilitating formation of a thermoreversible hydrogel. The ability of ions to impact the cloud point and gel strength generally followed the rank order of the Hofmeister series. Solid dispersions of CBZ and Soluplus® were prepared by KinetiSol® Dispersing, characterized to confirm an amorphous composition was formed and incorporated into tablets at very high levels (70% w/w). Dissolution studies demonstrated the utility of including salts in tablets to improve dissolution properties. Tablets that did not contain a salt or those that included a chaotropic salt hydrated at the tablet surface and did not allow for sufficient moisture ingress into the tablet. Conversely, the inclusion of kosmotropic salts allowed for rapid hydration of the entire tablet and the formation of a gel structure with strength dependent on the type of salt utilized. Studies also showed that, in addition to allowing tablet hydration, potassium bicarbonate and potassium carbonate provided effervescence which effectively destroyed the gel network and allowed for rapid dissolution of CBZ. Subsequent dissolution studies in 0.1N HCl showed that potassium bicarbonate was an effective tablet disintegrant at levels as low as 1% and provided for tablets that rapidly disintegrated over a wide range of applied compression forces, presumably due to synergy between the ability to form a weak hydrogel structure and carbon dioxide liberation. Similar dissolution performance was measured in pH 4.5 acetate buffer, despite reduced polymer solubility caused by kosmotropic salts in solution, demonstrating robustness. With the use of inorganic salts such as potassium bicarbonate, it may be possible to substantially improve disintegration and dissolution characteristics of tablets containing Soluplus®.

Spray Congealing of Pharmaceuticals: Study on Production of Solid Dispersions Using Box-Behnken Design

This work aimed at evaluating the spray congealing method for the production of microparticles of carbamazepine combined with a polyoxylglyceride carrier. In addition, the influence of the spray congealing conditions on the improvement of drug solubility was investigated using a three-factor, three-level Box-Behnken design. The factors studied were the cooling air flow rate, atomizing pressure, and molten dispersion feed rate. Dependent variables were the yield, solubility, encapsulation efficiency, particle size, water activity, and flow properties. Statistical analysis showed that only the yield was affected by the factors studied. The characteristics of the microparticles were evaluated using X-ray powder diffraction, scanning electron microscopy, differential scanning calorimetry, and hot-stage microscopy. The results showed a spherical morphology and changes in the crystalline state of the drug. The microparticles were obtained with good yields and encapsulation efficiencies, which ranged from 50 to 80% and 99.5 to 112%, respectively. The average size of the microparticles ranged from 17.7 to 39.4 µm, the water activities were always below 0.5, and flowability was good to moderate. Both the solubility and dissolution rate of carbamazepine from the spray congealed microparticles were remarkably improved. The carbamazepine solubility showed a threefold increase and dissolution profile showed a twofold increase after 60 min compared to the raw drug. The Box-Behnken fractional factorial design proved to be a powerful tool to identify the best conditions for the manufacture of solid dispersion microparticles by spray congealing.

Increasing the oral bioavailability of poorly water-soluble carbamazepine using immediate-release pellets supported on SBA-15 mesoporous silica

Background and methods:The aim of this study was to develop an immediate-release pellet formulation with improved drug dissolution and adsorption. Carbamazepine, a poorly water-soluble drug, was adsorbed into mesoporous silica (SBA-15-CBZ) via a wetness impregnation method and then processed by extrusion/spheronization into pellets. Physicochemical characterization of the preparation was carried out by scanning electron microscopy, transmission electron microscopy, nitrogen adsorption, small-angle and wide-angle x-ray diffraction, and differential scanning calorimetry. Flowability and wettability of the drug-loaded silica powder were evaluated by bulk and tapped density and by the angle of repose and contact angle, respectively. The drug-loaded silica powder was formulated into pellets to improve flowability.Results:With maximum drug loading in SBA-15 matrices determined to be 20% wt, in vitro release studies demonstrated that the carbamazepine dissolution rate was notably improved from both the SBA-15 powder and the corresponding pellets as compared with the bulk drug. Correspondingly, the oral bioavailability of SBA-15-CBZ pellets was increased considerably by 1.57-fold in dogs (P < 0.05) compared with fast-release commercial carbamazepine tablets.Conclusion:Immediate-release carbamazepine pellets prepared from drug-loaded silica provide a feasible approach for development of a rapidly acting oral formulation for this poorly water-soluble drug and with better absorption.

Enhancing Dissolution Rate of Carbamazepine via Cogrinding with Crospovidone and Hydroxypropylmethylcellulose

Carbamazepine belongs to the class II biopharmaceutical classification system (BCS) which is characterized by a high per-oral dose, a low aqueous solubility and a high membrane permeability. The bioavailability of such a drug is limited by the dissolution rate. In order to increase the drug dissolution, its solid dispersions were prepared by the cogrinding technique using an insoluble but highly hydrophilic crospovidone and soluble hydroxypropylmethylcellulose (HPMC) as the carriers. The ratios of drug to carrier were 1:1, 1:5 and 1:10. Comparison of the dissolution of the drug from its cogrounds with that of the unground drug, its ground form and the corresponding physical mixtures revealed considerable differences. The percentage of drug dissolved during the first 30 min, (%D 30 ), for the ground and coground drug was 75-95, whereas the %D 30 for unground drug and its physical mixtures ranged from 41-62. FT-IR spectra indicated no intraction between the drug and the carriers in the cogrounds. But reduced crystallinity of the drug in the ground and cogrounds was evident in the x-ray diffraction patterns. The decreased crystallinity together with a reduced particle size, enhanced deaggregation and increased wettability of the drug. This could be accounted for the increased dissolution from the cogrounds. From the dissolution point of view, the physical mixtures of HPMC were inferior to the cogrounds, but were slightly superior to the physical mixtures of crospovidone due to the solubilization effect of HPMC.

Glucosamine HCl as a new carrier for improved dissolution behaviour: Effect of grinding

The co-grinding technique is one of the most effective methods for improving the dissolution rate of poorly water-soluble drugs and it is superior to other approaches from an economical as well as an environmental stand point, as the technique does not require any toxic organic solvents. The present work is an attempt to use d-glucosamine HCl (G-HCl) as a potential excipient to improve dissolution rate of carbamazepine (CBZ) from physical mixtures and co-grinding formulations. The effect of order of grinding on dissolution of CBZ was also investigated. Co-ground of drug and G-HCL were prepared using different ratios using ball mill. The samples were subjected to different grinding times. In order to investigate the effect of grinding process on dissolution behaviour of CBZ, the drug was ground separately in the absence of glucosamine. Then the mixture of ground CBZ and un-ground d-glucosamine HCl were prepared. Physical mixtures of CBZ and G-HCl were also prepared for comparison. The properties of prepared co-ground systems and physical mixtures were studied using a dissolution tester, FT-IR, SEM, XRPD, and DSC. These results showed that the presence of glucosamine can increase dissolution rate of CBZ compared to pure CBZ. The results showed the order of grinding had a big impact on the dissolution performance of CBZ formulations containing glucosamine. All dissolution profiles generally showed that the fastest dissolution rate was obtained when ground CBZ was mixed with un-ground glucosamine. This was closely followed by the co-grinding of CBZ with glucosamine where lower grinding times showed the fastest dissolution. XRPD showed that the grinding of CBZ can reduce the percentage crystallinity of drug crystals. DSC study of ground CBZ showed that the grinding induced polymorphism transformations in the CBZ crystals and the limit and type of these transformations were related to the grinding time.