Oral Controlled-Release Dosage Forms. I. Cellulose Ether Polymers in Hydrophilic Matrices

Abstract

An appropriately designed controlled-release drug delivery system can be a major advance towarb solving problems concerning the targeting of a drug to a specific organ or tissue and controlling the rate of drug delivery to the target tissue. Hydrophilic matrices are an interesting option when developing an oral controlled-release formulation. The present study focuses on oral controlled-release dosage forms and the application of cellulose ether polymers in hydrophilic matrices. Key Words. Controlled-release matrices; Hydrophilic matrices; Cellulose ether polymers; Hydroxypropylmethylcellulose; HPMC     

Statistical Comparison of the Dissolution curves of Controlled-Release Solid Oral Dosage Forms

Abstract

This paper shows how the Box method, based on the statistical technique known as “split-plot” in general use for replicate measurements, may be used to quantify and compare in vitro dissolution curves of controlled release solid oral dosage forms. In this case, it is applied to the interpretation of the findings of a stability test on controlled-released lithium tablets formulated with a wax matrix and containing 10.8 mEq lithium per tablet. The findings showed that the total amount of lithium dissolved after the tablets had been stored for a period of six months was slightly greater than before storage; the dissolution mean rate went from 1.06 mEq/h to 1.17 mEq/h and the dissolution rate curve profile apparently registered less variation.

The method described here for the comparison of dissolution curves is particularly useful when the curves do not follow a set kinetic process and has proved sensitive to slight changes in the dissolution profile.     

Statistical Comparison of the Dissolution curves of Controlled-Release Solid Oral Dosage Forms

This paper shows how the Box method, based on the statistical technique known as “split-plot” in general use for replicate measurements, may be used to quantify and compare in vitro dissolution curves of controlled release solid oral dosage forms. In this case, it is applied to the interpretation of the findings of a stability test on controlled-released lithium tablets formulated with a wax matrix and containing 10.8 mEq lithium per tablet. The findings showed that the total amount of lithium dissolved after the tablets had been stored for a period of six months was slightly greater than before storage; the dissolution mean rate went from 1.06 mEq/h to 1.17 mEq/h and the dissolution rate curve profile apparently registered less variation.

The method described here for the comparison of dissolution curves is particularly useful when the curves do not follow a set kinetic process and has proved sensitive to slight changes in the dissolution profile.     

Synthetic PMMA-Grafted Polysaccharides as Hydrophilic Matrix for Controlled-Release Forms

This paper describes the rheological behavior of starch and cellulose acrylic graft copolymers synthesized with the aim of obtaining controlled-release excipients. The rheological characteristics determine the final release properties of matrix tablets. The study of the storage and loss moduli (G′ and G″, respectively) and the viscosity allowed us to know if the polymer behavior was that of a gel and, hence, if it could act as a barrier to drug diffusion. Since dynamic measurements showed a storage modulus higher than the loss modulus, we assessed that all the polymers were gels. Thus, knowing that all the graft copolymers had acceptable properties for compression, the release of theophylline as a model drug at different pH was studied. Polymers with higher absorption capacity, viscosity, and compactibility allowed formulations with slower release rates.     

Evaluation of Xanthan Cum as a Hydrophilic Matrix for Controlled-Release Dosage form Preparations

Abstract

Xanthan gum was evaluated as hydrophilic matrix for controlled release preparations. Different parameters were considered: direct and wet granulation, gum concentration, effect of addition of binders, pH, ionic strength, rotation speed and surfactant. Suitable controlled release profile could be obtained. Practically no influence of the parameters studied was noted, with the exception of gum concentration, the rotation speed and presence of ion in the dissolution medium. The release rate profiles were evaluated by different kinetic equations: Zero order, First order, Higuchi equation and RRSBW equation and the data statistically analyzed with F-Ratio. Without binder, in aqueous medium, zero order kinetics were found from the origin of the release rate profile. With binder and dissolution media with electrolytes or buffer solutions, generally zero order kinetics were also found after an initial period of about half an hour. The release kinetics were independent of the method of preparation and compression force.     

Evaluation of Xanthan Cum as a Hydrophilic Matrix for Controlled-Release Dosage form Preparations

Xanthan gum was evaluated as hydrophilic matrix for controlled release preparations. Different parameters were considered: direct and wet granulation, gum concentration, effect of addition of binders, pH, ionic strength, rotation speed and surfactant. Suitable controlled release profile could be obtained. Practically no influence of the parameters studied was noted, with the exception of gum concentration, the rotation speed and presence of ion in the dissolution medium. The release rate profiles were evaluated by different kinetic equations: Zero order, First order, Higuchi equation and RRSBW equation and the data statistically analyzed with F-Ratio. Without binder, in aqueous medium, zero order kinetics were found from the origin of the release rate profile. With binder and dissolution media with electrolytes or buffer solutions, generally zero order kinetics were also found after an initial period of about half an hour. The release kinetics were independent of the method of preparation and compression force.     

Oral Dosage Forms with Controlled Gastrointestinal Transit

Abstract

The present investigation concerns the development of new dosage forms which, after oral administration, exert an active influence on their gastrointestinal transit. The dosage forms release excipients which aim to increase the lenght of time the drug spends in the absorbing section of the duodenum and small intestine. A delayed gastrointestinal transit is intended to achieve a more complete and longer lasting absorption of drugs with a limited duration of absorption. The present study examined whether, by incorporating triethanolamine myristate (165 mg) as an excipient in tablets containing riboflavine (20 mg) as an example of a drug with limited absorption, the gastrointestinal transit of riboflavine could be delayed and hence its absorption improved. Five subjects took part in the in vivo studies and a pH-telemetering device (Heidelberg capsule) was used to determine gastric residence time.

The investigations showed that in 4 out of 5 subjects, the gastric residence time of the pH-telemetering capsule could be prolonged and the renal elimination of riboflavine increased The increase in renal elimination of riboflavine in the presence of triethanolamine myristate was statistically significant in the 4th urine collection period (0.05 > p> 0.0025).     

Dissolution of Omeprazole from Delayed-Release Solid Oral Dosage Forms

The evaluation of the biopharmaceutical quality of omeprazole enteric-coated products (granules in capsules) with respect to its dissolution characteristics is not specifically regulated in any of the most common official pharmacopoeia. USP 23 includes a general monograph for enteric-coated products. This paper reports the evaluation of the medium pH effect on the dissolution rates of omeprazole from four omeprazole-containing products of different manufacturers. It is concluded that the USP 23 recommended dissolution procedure for enteric-coated products is not suitable due to the degradation of omeprazole under such conditions. Furthermore, the medium with pH 8.0 showed different dissolution rates not observed at pH 7.4, allowing discrimination between products of different manufacturers.     

Dissolution Profiling of Six Modified-Release Oral Solid Dosage Forms

Abstract

Dissolution testing was conducted for six non-combination, single entity, modified-release oral solid dosage forms. Dissolution medium was water and 0.1 N hydrochloric acid. USP Apparatus 1 and Apparatus 2 were used arid were rotated at either 50 or 100 rpm. A complete dissolution profile was obtained for all six dosage forms based on their stated dosing interval, D. The three strengths of Theo-dur tablets, Norpace CR 150 mg capsules, and the two strengths of Chlor-trimeton tablets passed the Compendial Case One requirements (USP XXI, 2S, 1906). Thorazine spansules and Quinidex tablets were unable to meet the specifications with water as the dissolution medium; the latter showed improved dissolution character in 0.1 N hydrochloric acid. Tenuate Dospan 75 mg tablets showed good release characteristics in water when the authentic (dosing interval (D = 24 hours) was changed to a modified dosing interval of D* = 12 hours. All dissolution aliquots were assayed by UV absorbance measurements at the absorbance maximum for each drug and were also checked for excipient interference. Newer drugs appearing on the market will be more likely candidates for meeting compendial specifications; modified-release pharmaceuticals that appeared before the new specifications may have to be allocated specifically expanded window percentages.     

Sensory Analysis of Liquid Oral Dosage Forms Antacid Suspensions

Sensory analysis of pharmaceutical oral dosage forms can be used effectively in product development and quality control to improve patient acceptance of the drug. In this work, sensory analysis is applied to detect consumer preference for formulations of aluminum and magnesium hydroxide antacid suspensions. A ranking test was applied to six peppermint flavored commercial samples (identified from A to F) of the antacid with the same therapeutical potency. The samples corresponded to four different formulations and six batches from three manufacturers. The ranking test was applied in duplicate to ten judges (ages 20–34) trained in the method and in the main sensory characteristics of the product. The coded samples were presented randomly in duplicate to each judge with six replications, and results were recorded in a preference scale from 1 to 6 (1 = most preferred). Statistical analysis of the data considered the sample as the only cause for variation and the minimum significant difference was determined at confidence levels of α = 0.01 and α = 0.05. The results show a highly significant preference (α = 0.01) in sample F over A, B, D and E. At α = 0.05, sample F was preferred over all the others, whereas formulations A and D were the least preferred at both significance levels. These results demonstrate that sensory analysis can be applied succesfully in product selection for the patient, formulation development and as a quality control tool in antacid suspensions.     

Dissolution Profiling of Six Modified-Release Oral Solid Dosage Forms

Dissolution testing was conducted for six non-combination, single entity, modified-release oral solid dosage forms. Dissolution medium was water and 0.1 N hydrochloric acid. USP Apparatus 1 and Apparatus 2 were used arid were rotated at either 50 or 100 rpm. A complete dissolution profile was obtained for all six dosage forms based on their stated dosing interval, D. The three strengths of Theo-dur tablets, Norpace CR 150 mg capsules, and the two strengths of Chlor-trimeton tablets passed the Compendial Case One requirements (USP XXI, 2S, 1906). Thorazine spansules and Quinidex tablets were unable to meet the specifications with water as the dissolution medium; the latter showed improved dissolution character in 0.1 N hydrochloric acid. Tenuate Dospan 75 mg tablets showed good release characteristics in water when the authentic (dosing interval (D = 24 hours) was changed to a modified dosing interval of D* = 12 hours. All dissolution aliquots were assayed by UV absorbance measurements at the absorbance maximum for each drug and were also checked for excipient interference. Newer drugs appearing on the market will be more likely candidates for meeting compendial specifications; modified-release pharmaceuticals that appeared before the new specifications may have to be allocated specifically expanded window percentages.     

Role of Cellulose Ether Polymers on Ibuprofen Release from Matrix Tablets

Cellulose derivatives are the most frequently used polymers in formulations of pharmaceutical products for controlled drug delivery. The main aim of the present work was to evaluate the effect of different cellulose substitutions on the release rate of ibuprofen (IBP) from hydrophilic matrix tablets. Thus, the release mechanism of IBP with methylcellulose (MC25), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K15M or K100M) was studied. In addition, the influence of the diluents lactose monohydrate (LAC) and β-cyclodextrin (β-CD) was evaluated. Distinct test formulations were prepared containing: 57.14% of IBP, 20.00% of polymer, 20.29% of diluent, 1.71% of talc lubricants, and 0.86% of magnesium stearate as lubricants. Although non-negligible drug-excipient interactions were detected from DSC studies, these were found not to constitute an incompatibility effect. Tablets were examined for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, swelling, and dissolution performance. Polymers MC25 and HPC were found to be unsuitable for the preparation of this kind of solid dosage form, while HPMC K15M and K100M showed to be advantageous. Dissolution parameters such as the area under the dissolution curve (AUC), the dissolution efficiency (DE_{20 h}), dissolution time (t 50%), and mean dissolution time (MDT) were calculated for all the formulations, and the highest MDT values were obtained with HPMC indicating that a higher value of MDT signifies a higher drug retarding ability of the polymer and vice-versa. The analysis of the drug release data was performed in the light of distinct kinetic mathematical models—Kosmeyer-Peppas, Higuchi, zero-, and first-order. The release process was also found to be slightly influenced by the kind of diluent used.     

Evaluation of Dosage Forms. VI. Studies of Commercial Oxyphenbutazone Tablet Dosage Forms

Dissolution-dialysis studies of commercial tablets of oxyphenbutazone were carried out to establish the applicability of this technique for the in vitro evaluation of oxyphenbutazone dosage form. While disintegration time and dissolution rate studies did not give a true indication of bioavailability, an excellent correlation was obtained between the dialysis rate constant K and the pharmacokinetic parameters AUC and C_max.     

Comparative pH-Gradient Dissolution of Several Oral Dosage Forms of Iron

Abstract

A comparative pH - gradient dissolution study was conducted for several brands of oral iron dosage forms on the Canadian market. The commercially available dissolution apparatus employed in the study met the requirements of the variety of pH media conditions necessary for conducting dissolution of conventional, enteric coated and slow release iron preparations. The reproducibility of the dissolution system was evaluated using the USP's non-disintegrating salicylic acid tablets. Dissolution results are discussed in reference to a recent bioavailability report concerning oral iron preparations. The applicability of the procedure in studying the dissolution of solid dosage forms of iron is discussed.     

Comparative pH-Gradient Dissolution of Several Oral Dosage Forms of Iron

A comparative pH - gradient dissolution study was conducted for several brands of oral iron dosage forms on the Canadian market. The commercially available dissolution apparatus employed in the study met the requirements of the variety of pH media conditions necessary for conducting dissolution of conventional, enteric coated and slow release iron preparations. The reproducibility of the dissolution system was evaluated using the USP's non-disintegrating salicylic acid tablets. Dissolution results are discussed in reference to a recent bioavailability report concerning oral iron preparations. The applicability of the procedure in studying the dissolution of solid dosage forms of iron is discussed.     

Use of a Moist Granulation Technique (MGT) to Develop Controlled-Release Dosage Forms of Acetaminophen

The moist granulation technique (MGT), which involves agglomeration and moisture absorption, has only been applied to immediate-release dosage forms. Our results indicate that MGT appears to be applicable in developing a controlled-release formulation. A small amount of granulating fluid (water) was added to a powder blend to activate a dry binder (such as polyvinylpyrrolidone [PVP] at 2% and 3.6%) and to facilitate agglomeration. Then, a moisture-absorbing material (microcrystalline cellulose [MCC]) was added to absorb any excess moisture. By adding MCC in this way, a drying step was not necessary. Acetaminophen (APAP) was the model drug, with diluents lactose FastFlo® and dicalcium phosphate. Hydroxypropylcellulose (HPC) was used as the controlled-release agent. The MGT was compared to conventional wet granulation (WG) and direct compression (DC) processing methods. The results indicate that MGT appears to be applicable in developing a controlled-release formulation. Particle size distribution of MGT and WG batches containing 3.6% PVP is similar.     

Use of a Moist Granulation Technique (MGT) to Develop Controlled-Release Dosage Forms of Acetaminophen

The moist granulation technique (MGT), which involves agglomeration and moisture absorption, has only been applied to immediate-release dosage forms. Our results indicate that MGT appears to be applicable in developing a controlled-release formulation. A small amount of granulating fluid (water) was added to a powder blend to activate a dry binder (such as polyvinylpyrrolidone [PVP] at 2% and 3.6%) and to facilitate agglomeration. Then, a moisture-absorbing material (microcrystalline cellulose [MCC]) was added to absorb any excess moisture. By adding MCC in this way, a drying step was not necessary. Acetaminophen (APAP) was the model drug, with diluents lactose FastFlo® and dicalcium phosphate. Hydroxypropylcellulose (HPC) was used as the controlled-release agent. The MGT was compared to conventional wet granulation (WG) and direct compression (DC) processing methods. The results indicate that MGT appears to be applicable in developing a controlled-release formulation. Particle size distribution of MGT and WG batches containing 3.6% PVP is similar.     

Development of Controlled-Release Buccoadhesive Hydrophilic Matrices of Diltiazem Hydrochloride: Optimization of Bioadhesion,Dissolution, and Diffusion Parameters

ABSTRACT

Buccoadhesives have long been employed to improve the bioavailability of drugs undergoing significant hepatic first-pass metabolism. Diltiazem hydrochloride (DLZ) is also reported to have low oral bioavailability due to an extensive hepatic first-pass effect. Controlled-release buccoadhesive hydrophilic matrices containing DLZ were prepared using a 3² factorial design. Amounts of Carbopol® 934P (CP) and Methocel® K100LV (HPMC) were taken as the formulation variables (factors) for optimizing bioadhesion, and kinetics of dissolution and diffusion. A mathematical model was generated for each response parameter. Bioadhesive strength tended to vary quite linearly in increasing order with increasing amount of each polymer. The drug release pattern for all the formulation combinations was found to be non-fickian, approaching zero-order kinetics. The values of permeation coefficient tended to vary non-linearly with polymer amount, depicting the plausibility of interaction between the two polymers. Suitable combinations of the two polymers provided adequate bioadhesive strength and a fairly regulated release profile up to 10 hr. The response surfaces and contour plots for each response parameter are presented for further interpretation of the results. The optimum formulations were chosen and their predicted results found to be in close agreement with experimental findings.     

Disintegrants in Solid Dosage Forms

The dynamic approach to tablet disintegration, which is based on the measurement of the force that develops inside the compact upon water entrance, is basically taken up.

The combined measurements of force development and water uptake, simultaneously effected on the same compact, provide a novel parameter that is proposed to quantify and compare the efficiency of disintegrants.

The new parameter, which is based on the “force-equivalent” concept, expresses the capability of a disintegrant of transforming water uptaken into swelling (or disintegrating) force. A few examples, that illustrate the usefulness of this parameter for disintegrant characterization, are given.

In parallel to the quantification of swelling (or disintegrating) efficiency inside compacts, attention is also being paid to the characterization of swelling disintegrants as pure materials.

In particular the case of the so-called limited swelling materials, for which the quantification of intrinsic swelling (particle volume increase in swelling media) is critical, is considered.

The applicability of an instrumental method, which is based on the employment of a Coulter Counter, is discussed alternatively to microscopic methods.

Disintegrant characterization may also be considered in view of new possible exploitations of the swelling properties of polymers in controlling drug release.     

Disintegrants in Solid Dosage Forms

Abstract

The dynamic approach to tablet disintegration, which is based on the measurement of the force that develops inside the compact upon water entrance, is basically taken up.

The combined measurements of force development and water uptake, simultaneously effected on the same compact, provide a novel parameter that is proposed to quantify and compare the efficiency of disintegrants.

The new parameter, which is based on the “force-equivalent” concept, expresses the capability of a disintegrant of transforming water uptaken into swelling (or disintegrating) force. A few examples, that illustrate the usefulness of this parameter for disintegrant characterization, are given.

In parallel to the quantification of swelling (or disintegrating) efficiency inside compacts, attention is also being paid to the characterization of swelling disintegrants as pure materials.

In particular the case of the so-called limited swelling materials, for which the quantification of intrinsic swelling (particle volume increase in swelling media) is critical, is considered.

The applicability of an instrumental method, which is based on the employment of a Coulter Counter, is discussed alternatively to microscopic methods.

Disintegrant characterization may also be considered in view of new possible exploitations of the swelling properties of polymers in controlling drug release.