Chitosan and sodium sulfate as excipients in the preparation of prolonged release theophylline tablets

The major objectives of this study were to monitor the effect of cross-linking of cationic chitosan in acidic media with sulfate anion during granules preparation by wet granulation method prior to tableting using theophylline (TPH) as a model drug. The prepared granules and the compressed tablets were subjected to in vitro evaluation. The properties of the prepared matrix granules and the compressed tablets were dependent on chitosan:sodium sulfate weight ratios, chitosan content, and molecular weight of chitosan. The prepared granules of all batches showed excellent to passable flowability and were suitable for compression into tablets. Most of the granules were hard and expected to withstand handling during the subsequent compression into tablets. Granules with high friabilities were only those prepared with a high amount of sodium sulfate or low amount of chitosan. Compression of granule batches yield nondisintegrating tablets that showed a decrease in tensile strength with the increase of sodium sulfate content at high chitosan:sodium sulfate weight ratio or with decrease of chitosan content. On the other hand, friability of tablets was increased in the presence of an excessive amount of sodium sulfate and low chitosan content as observed with granules. Slow TPH release from the formulated tablets was achieved at 1:0.5 and 1:1 chitosan:sodium sulfate weight ratios where all or most of the cationic chitosan and sulfate anions were used in a cross-linking reaction during wet granulation. Ratios of 1:2 and 1:3 showed fast drug release, which support the hypothesis that excessive unreacted water-soluble sodium sulfate might increase the porosity of the nondesintegrating tablets during dissolution. Slow drug release was also obtained with high molecular weight chitosan, whereas changing the hardness of the tablets did not significantly change the release profile of the drug as long as the tablets are intact during dissolution. Furthermore, slow drug release was observed as the total amount of chitosan was increased in the formulated tablets. A comparative in vivo study between the chosen formulated tablets (1:1 chitosan:sodium sulfate ratio that contains 10% high molecular weight chitosan) and the commercial Quibron tablets indicated prolonged appearance of the drug in dogs' plasma for both formulations with no significant differences (p > 0.05) in rate and extent of drug absorption. The formulated tablets showed 103.16% bioavailability relative to that of the commercial tablets.     

Excipient-excipient interaction in the design of sustained-release theophylline tablets: in vitro and in vivo evaluation

Sustained-release (SR) theophylline (TPH) tablets were prepared by applying the moisture-activated dry granulation method. The interaction between the excipients sodium alginate (SAL) and calcium gluconate (CG) was the base for the formation of a cross-linked matrix that may regulate TPH release from the formulated tablets. The prepared granules showed good physical characteristics concerning the flow properties and compressibility, with the angles of repose in the range 29-31, and the compressibility indices ranged between 15% and 25%. The granules had low friability values (3.0%-4.2%), depending on SAL:CG ratios. The corresponding tablets showed good physical properties, with a lower rate of drug release compared with the commercial TPH tablets (Quibron®). The release of TPH from the prepared tablets was not markedly affected by either the concentration of added dry binder (carbopol 934) or the tablet hardness, indicating that the rate-determining step in drug release was the diffusion through the produced calcium alginate matrix. Tablets formulated with equal ratios of CG and SAL that showed good physical properties and slow TPH release were chosen for bioavailability studies in beagle dogs, and results were compared with those for Quibron. The in vivo data showed a comparable plasma concentration profile for both tablet formulations, with prolonged appearance of drug in the plasma in detectable amounts for up to 24 h. The formulated tablets showed 104.65% bioavailability relative to that of the commercial tablets. The rate and extent of absorption of TPH showed no significant differences from that of the commercial tablets. Moreover, no significant differences were found in the pharmacokinetic parameters related to the rate and extent of TPH absorption from the prepared and commercial tablets.     

Excipient-Excipient Interaction in the Design of Sustained-Release Theophylline Tablets: In Vitro and In Vivo Evaluation

Sustained-release (SR) theophylline (TPH) tablets were prepared by applying the moisture-activated dry granulation method. The interaction between the excipients sodium alginate (SAL) and calcium gluconate (CG) was the base for the formation of a cross-linked matrix that may regulate TPH release from the formulated tablets. The prepared granules showed good physical characteristics concerning the flow properties and compressibility, with the angles of repose in the range 29–31, and the compressibility indices ranged between 15% and 25%. The granules had low friability values (3.0%–4.2%), depending on SAL:CG ratios. The corresponding tablets showed good physical properties, with a lower rate of drug release compared with the commercial TPH tablets (Quibron®). The release of TPH from the prepared tablets was not markedly affected by either the concentration of added dry binder (carbopol 934) or the tablet hardness, indicating that the rate-determining step in drug release was the diffusion through the produced calcium alginate matrix. Tablets formulated with equal ratios of CG and SAL that showed good physical properties and slow TPH release were chosen for bioavailability studies in beagle dogs, and results were compared with those for Quibron. The in vivo data showed a comparable plasma concentration profile for both tablet formulations, with prolonged appearance of drug in the plasma in detectable amounts for up to 24 h. The formulated tablets showed 104.65% bioavailability relative to that of the commercial tablets. The rate and extent of absorption of TPH showed no significant differences from that of the commercial tablets. Moreover, no significant differences were found in the pharmacokinetic parameters related to the rate and extent of TPH absorption from the prepared and commercial tablets.     

Spray-Dried Chitosan as a Direct Compression Tableting Excipient

The objective of this study was to prepare and evaluate a novel spray-dried tableting excipient using a mixture of chitosan and lactose. Three different grades of chitosan (low-, medium-, and high-molecular-weight) were used for this study. Propranolol hydrochloride was used as a model drug. A specific amount of chitosan (1, 1.9, and 2.5 g, respectively) was dissolved in 50 mL of an aqueous solution of citric acid (1%) and later mixed with 50 mL of an aqueous solution containing lactose (20, 19.1, and 18.5 g, respectively) and propanolol (2.2 g). The resultant solution was sprayed through a laboratory spray drier at 1.4 mL/min. The granules were evaluated for bulk density, tap density, Carr index, particle size distribution, surface morphology, thermal properties, and tableting properties. Bulk density of the granules decreased from 0.16 to 0.13 g/mL when the granules were prepared using medium- or high-molecular-weight chitosan compared with the low-molecular-weight chitosan. The relative proportion of chitosan also showed a significant effect on the bulk density. The granules prepared with 1 g of low-molecular-weight chitosan showed the minimum Carr index (11.1%) indicating the best flow properties among all five formulations. All three granules prepared with 1 g chitosan, irrespective of their molecular weight, showed excellent flow properties. Floating tablets prepared by direct compression of these granules with sodium bicarbonate showed 50% drug release between 30 and 35 min. In conclusion, the spray-dried granules prepared with chitosan and lactose showed excellent flow properties and were suitable for tableting.     

Spray-dried chitosan as a direct compression tableting excipient

The objective of this study was to prepare and evaluate a novel spray-dried tableting excipient using a mixture of chitosan and lactose. Three different grades of chitosan (low-, medium-, and high-molecular-weight) were used for this study. Propranolol hydrochloride was used as a model drug. A specific amount of chitosan (1, 1.9, and 2.5 g, respectively) was dissolved in 50 mL of an aqueous solution of citric acid (1%) and later mixed with 50 mL of an aqueous solution containing lactose (20, 19.1, and 18.5 g, respectively) and propanolol (2.2 g). The resultant solution was sprayed through a laboratory spray drier at 1.4 mL/min. The granules were evaluated for bulk density, tap density, Carr index, particle size distribution, surface morphology, thermal properties, and tableting properties. Bulk density of the granules decreased from 0.16 to 0.13 g/mL when the granules were prepared using medium- or high-molecular-weight chitosan compared with the low-molecular-weight chitosan. The relative proportion of chitosan also showed a significant effect on the bulk density. The granules prepared with 1 g of low-molecular-weight chitosan showed the minimum Carr index (11.1%) indicating the best flow properties among all five formulations. All three granules prepared with 1 g chitosan, irrespective of their molecular weight, showed excellent flow properties. Floating tablets prepared by direct compression of these granules with sodium bicarbonate showed 50% drug release between 30 and 35 min. In conclusion, the spray-dried granules prepared with chitosan and lactose showed excellent flow properties and were suitable for tableting.     

Chitosan Matrix Tablets: The Influence of Excipients on Drug Release

The influence of excipients on drug release from chitosan matrix tablets was investigated, using diltiazem hydrochloride as model drug. Tablets were prepared by direct compression and the effect of different concentrations of the excipients lactose, sodium lauryl sulphate, sodium alginate, carbopol 934, citric acid and hydroxypropylmethyl-cellulose on drug release profiles was studied. Sustained release of the drug was obtained in all cases but the results indicate that both type and amount of excipient used influences drug release rate. The results support the idea that chitosan can be suitable as a basis for sustained release matrix tablets, and that drug release rate can be influenced by the addition of excipients. It is possible to make use of the interaction between chitosan and excipients in the formulation to provide further prolongation of release.     

Chitosan Matrix Tablets: The Influence of Excipients on Drug Release

Abstract

The influence of excipients on drug release from chitosan matrix tablets was investigated, using diltiazem hydrochloride as model drug. Tablets were prepared by direct compression and the effect of different concentrations of the excipients lactose, sodium lauryl sulphate, sodium alginate, carbopol 934, citric acid and hydroxypropylmethyl-cellulose on drug release profiles was studied. Sustained release of the drug was obtained in all cases but the results indicate that both type and amount of excipient used influences drug release rate. The results support the idea that chitosan can be suitable as a basis for sustained release matrix tablets, and that drug release rate can be influenced by the addition of excipients. It is possible to make use of the interaction between chitosan and excipients in the formulation to provide further prolongation of release.     

Carbamazepine Modified Release Dosage Forms

The preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.

These formulations were obtained in two different steps:

a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid - methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.

b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.

In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was observed.

In vitro dissolution tests of sustained release dosage forms, performed varying during the test, the pH of the dissolution medium, (hydrochloric acid pH 1 from 0 to 2 hours and phosphate buffer pH 6.8 from 2 to 18 hours) showed that the determining factors in the controlling release of the drug are: the type and amount of enteric polymer constituting the granules and the amount of hydroxy-propylmethylcellulose mixed with them.     

Investigation of Prolonged Drug Release from Matrix Formulations of Chitosan

A hydrocolloidal matrix system containing complexes of chitosan was investigated for preparation of sustained release tablets and examined in-vitro.

Theophylline tablets using chitosan as a sustained release base were evaluated. It was found that when chitosan is used in a concentration of more than 50% of tablet weight, an insoluble non-erosion type matrix was formed. Tablets prepared with a chitosan concentration of less than 33% were fast releasing.

Chitosan used in a concentration of about 10% acted as a disintegrant and the drug was dissolved within an hour.

Citric acid slowed down the release rates of chitosan based theophylline tablets. Theophylline tablets using carbomer-934P as a sustained release base were evaluated. Carbomer-934P in lower concentrations forms an erosion type matrix. In order to produce a twenty-four (24) hour sustained release tablet, more than 10% concentration of carbomer-934P is needed. Combination with chitosan and carbomer-934P produced slower releasing tablets.

A hydrocolloidal erosion type matrix was formulated using chitosan, carbomer-934Pand citric acid. Only 10% of chitosan was needed to prepare theophylline sustained release tablets in these mixtures.

The dose dumping potential of chitosan tablets due to rapid disintegration in alkaline media was eliminated by preparing hydrated erosion type matrix systems.     

Carbamazepine Modified Release Dosage Forms

Abstract

The preparation of sustained release dosage forms of Carbamazepine (anti-epileptic drug characterized by a very low water solubility and by a short half life on chronique dosing) was carried out.

These formulations were obtained in two different steps:

a) modified release granules were prepared by the loading of cross-linked sodium carboxymethylcellulose (swellable polymer), with the drug and an enteric polymer. Cellulose acetate phthalate, methacrylic acid – methacrylic acid methyl ester copolymer (usually employed as enteric coating agents) and cellulose acetate trimellitate (a new enteric polymer) were used in different weight ratios.

b) some sustained release dosage forms were prepared tabletting physical mixtures of the modified release granules with different weight ratios of hydroxypropylmethylcellulose.

In vitro dissolution tests of modified release granules in gastric fluid (USP XXI) showed a modulation of the drug release, while in intestinal fluid (USP XXI) a quick drug dissolution was observed.

In vitro dissolution tests of sustained release dosage forms, performed varying during the test, the pH of the dissolution medium, (hydrochloric acid pH 1 from 0 to 2 hours and phosphate buffer pH 6.8 from 2 to 18 hours) showed that the determining factors in the controlling release of the drug are: the type and amount of enteric polymer constituting the granules and the amount of hydroxy-propylmethylcellulose mixed with them.     

A Study on the Manufacture and in Vitro Dissolution of Terbutaline Sulfate Microcapsules and their Tablets

Microcapsules of terbutaline sulfate with cellulose acetate butyrate and ethylcellulose were prepared using an emulsion-solvent evaporation technique. The in vitro dissolution of terbutaline sulfate was studied using the USP rotating basket method. As the polymer to drug ratio increased, the microcapsule size distribution shifted to the smaller size and the release of terbutaline sulfate decreased. The release of terbutaline sulfate was independent of the dissolution medium pH for both polymers. The release kinetics from the microcapsules was dependent on the polymer type and polymer to drug ratio. The release of terbutaline sulfate from cellulose acetate butyrate and ethylcellulose microcapsules formulated with a 1:1 polymer to drug ratio was complex and could not be differentiated between the square-root of time and first-order release models. However, the square-root of time model was followed by microcapsules formulated with a 2:1 or a 3:1 cellulose acetate butyrate to drug ratio. When the ethylcellulose to drug ratio was increased to 2:1 the square-root of time model was followed. At an ethylcellulose to drug ratio of 3:1 the release kinetics could not be differentiated between the Hixon-Crowell and first-order release models. The T50% from ethylcellulose microcapsules was decreased when the microcapsules were compressed into tablets with the addition of Avicel^R/Emcompress^R (2:1) or Avicel^R.     

A Study on the Manufacture and in Vitro Dissolution of Terbutaline Sulfate Microcapsules and their Tablets

Abstract

Microcapsules of terbutaline sulfate with cellulose acetate butyrate and ethylcellulose were prepared using an emulsion-solvent evaporation technique. The in vitro dissolution of terbutaline sulfate was studied using the USP rotating basket method. As the polymer to drug ratio increased, the microcapsule size distribution shifted to the smaller size and the release of terbutaline sulfate decreased. The release of terbutaline sulfate was independent of the dissolution medium pH for both polymers. The release kinetics from the microcapsules was dependent on the polymer type and polymer to drug ratio. The release of terbutaline sulfate from cellulose acetate butyrate and ethylcellulose microcapsules formulated with a 1:1 polymer to drug ratio was complex and could not be differentiated between the square-root of time and first-order release models. However, the square-root of time model was followed by microcapsules formulated with a 2:1 or a 3:1 cellulose acetate butyrate to drug ratio. When the ethylcellulose to drug ratio was increased to 2:1 the square-root of time model was followed. At an ethylcellulose to drug ratio of 3:1 the release kinetics could not be differentiated between the Hixon-Crowell and first-order release models. The T50% from ethylcellulose microcapsules was decreased when the microcapsules were compressed into tablets with the addition of Avicel^R/Emcompress^R (2:1) or Avicel^R.     

Application of moisture activated dry granulation (MADG) process to develop high dose immediate release (IR) formulations

Moisture activated dry granulation (MADG) method was used to develop IR tablets with cohesive, fluffy and high dose drugs. To evaluate this approach, three drugs: metformin hydrochloride, acetaminophen and ferrous ascorbate were selected as model compound along with three binders: maltodextrin DE16, PVP K 12 and HPC. The granules were generated using MADG method and tablets were prepared using rotary tablet press. The granules and tablets were characterized for particle size analysis, flow properties, tablet hardness, friability, moisture content, dissolution study, disintegration time and stability study. All results were found to be within acceptable limits. Development of all formulation tablets were found as best fitted for an immediate release of Metformin hydrochloride, acetaminophen and ferrous ascorbate. MADG delivered a robust manufacturing process for generation of granules with excellent flowability. The tablets prepared using this method were found to show better content uniformity, good compactability and low friability. Use of this approach aids to lower the amount of excipients used to overcome physiochemical limitation of the drug substances and there side effects. Both drying and milling steps in wet granulation were not required for MADG process. MADG became a cost effective process which could lead to reduced total tablet size and also save time.     

Influence of natural polymer coating on novel colon targeting drug delivery system

A novel colon targeted tablet formulation was developed using natural polysaccharides such as chitosan and guar gum as carriers and diltiazem hydrochloride as model drug. The prepared blend of polymer-drug tablets were coated with two layers, inulin as an inner coat followed by shellac as outer coat and were evaluated for properties such as average weight, hardness and coat thickness. In vitro release studies of prepared tablets were carried out for 2 h in pH 1.2 HCl buffer, 3 h in pH 7.4 phosphate buffer and 6 h in simulated colonic fluid (SCF) in order to mimic the conditions from mouth to colon. It was observed that 4% w/v of rat cecal contents in saline phosphate buffer (SCF) incubated for 24 h provides suitable conditions for in vitro evaluation of the formulations prepared. The drug release from the coated system was monitored using UV/ Visible spectroscopy. In vitro studies revealed that the tablets coated with inulin and shellac have controlled the drug release in stomach and small intestinal environment and released maximum amount of drug in the colonic environment. Among the polymers used, chitosan was found to be the suitable polymer for colon targeting. The study revealed that polysaccharides as carriers and inulin and shellac as coating materials can be used effectively for colon targeting of drugs for treating local as well as systemic disorders.     

Incorporation of calcium salts into xanthan gum matrices: hydration,erosion and drug release characteristics

Xanthan gum (XG), a hydrophilic biopolymer with modified release properties, was used to produce directly compressed matrix tablets containing a model drug, sodium p-aminosalicylate. Three formulations were prepared, each containing a different calcium dihydrate salt: calcium chloride, calcium sulfate or dibasic calcium phosphate. The aim of the investigation was to relate the calcium ion content and solubility of the calcium salt to the in vitro drug release profile of the xanthan matrices. Tablet hydration, erosion and drug release were determined in distilled water using the British Pharmacopoeia (BP) paddle method. The data showed that the overall drug release was the greatest with addition of calcium sulfate, followed by calcium chloride and dibasic calcium phosphate. The chloride salt formulation displayed the greatest percentage erosion due to rapid mass loss during the initial phase, followed by those with sulfate or phosphate salts. As xanthan gel viscosity increased and drug release was also found to be lower, it can be concluded that drug release is influenced by the solubility of the salt present in the formulation, since these parameters determine the viscosity and structure of the gel layer.     

Aging of Tablets Prepared by Direct Compression of Bases with Different Moisture Content

Abstract

Properties of aged tablets prepared by the wet granulation method were found to be affected by the moisture content of the granules. In this study, the storage-induced changes in hardness, disintegration and drug release were evaluated for tablets made by direct compression of three different bases with different initial moisture content. Tablets with high initial moisture content were found to increase in hardness upon storage. The magnititude of such increase is dependant upon the physical properties of the base and the absolute moisture content. The increase in hardness may increase the disintegration time and decrease drug release. Tablets with low initial moisture content were minimally affected by storage. The gain of moisture by some of these tablets led to enhancement in disintegration and drug release. Among the tablets studied lactose based tablets with different initial moisture content were found to be the most resistant to changes upon storage.     

Chitosan as a tablet binder

Abstract

Chitosan was evaluated as a binder for chlorpheniramine maleate tablets in comparison with other cellulose binders such as sodium carboxymethylcellulose, hydroxypropylmethylcellulose and methylcellulose. The effects of binder concentration on the mechanical properties of granules and tablets as well as on disintegration time and dissolution profiles were studied. Results showed that granules prepared with methylcellulose had lowest percentage of fines and friability. Chitosan tablets showed best dissolution profiles. The rank order correlation for binder efficiency was: hydroxypropylmethylcellulose > chitosan > methylcellulose > sodium carboxymethylcellulose.     

Chitosan formulations for steroid delivery: effect of formulation variables on in vitro characteristics

Chitosan film formulations for steroid delivery after craniomaxillofacial surgery were formulated by using three different types of chitosan with respect to their molecular weight as low, medium and high. Film formulations were prepared by casting/solvent evaporation technique. In vitro characterization, film thickness, equilibrium swelling degree, in vitro release profiles and surface morphologies were investigated. For two different types of crosslinkings, the release of dexamethasone sodium phosphate (DSP) can be extended as the molecular weight increases. As a result, chitosan film formulations should be beneficial for steroid delivery for a certain time after craniomaxillofacial surgery.     

Release Kinetics and Availability of Mebeverine Hydrochloride from Polycarbophil Loaded by Swelling

The release rate and mechanism of release of mebeverine hydrochloride were studied for commercial “Duspatalin” tablets and for different tablet formulations (F₁, F₂ & F₃) containing 20, 40 and 65% polycarbophil, respectively. The formulated granules were obtained by freeze drying of polycarbophil granules loaded with aqueous solution of the drug at 25°C by swelling of the polymer. The release of mebeverine hydrochloride from prepared tablet formulations was faster than that of Duspatalin tablets. The release rate of the drug increased as the polycarbophil content of the tablets increased. The calculated correlation coefficients for the release data fitted to various models showed that the release from Duspatalin tablets and F₂ follow first order kinetics, while release of F₁ approaches that of zero order. The release mechanism from F₃ could not be determined. DSC thermograms showed that there is an interaction between the drug and the polymer in aqueous medium, but not in the solid state.

The in-vivo guinea-pig studies revealed that mebeverine hydrochloride was released and absorbed from the tested formula (F₃), depressed the agonists-induced contractions 2 hrs after treatment but not after 4 hrs indicating rapid absorption and metabolism. The percentage inhibitions ranged from 40-85%. The treatment seems to antagonise barium chloride (BaCl₂)-induced contractions more than those induced by carbochol.     

Release Kinetics and Availability of Mebeverine Hydrochloride from Polycarbophil Loaded by Swelling

The release rate and mechanism of release of mebeverine hydrochloride were studied for commercial “Duspatalin” tablets and for different tablet formulations (F₁, F₂ & F₃) containing 20, 40 and 65% polycarbophil, respectively. The formulated granules were obtained by freeze drying of polycarbophil granules loaded with aqueous solution of the drug at 25°C by swelling of the polymer. The release of mebeverine hydrochloride from prepared tablet formulations was faster than that of Duspatalin tablets. The release rate of the drug increased as the polycarbophil content of the tablets increased. The calculated correlation coefficients for the release data fitted to various models showed that the release from Duspatalin tablets and F₂ follow first order kinetics, while release of F₁ approaches that of zero order. The release mechanism from F₃ could not be determined. DSC thermograms showed that there is an interaction between the drug and the polymer in aqueous medium, but not in the solid state.

The in-vivo guinea-pig studies revealed that mebeverine hydrochloride was released and absorbed from the tested formula (F₃), depressed the agonists-induced contractions 2 hrs after treatment but not after 4 hrs indicating rapid absorption and metabolism. The percentage inhibitions ranged from 40–85%. The treatment seems to antagonise barium chloride (BaCl₂)-induced contractions more than those induced by carbochol.