Preformulation the Role of Moisture in Solid Dosage Forms

Moisture plays an important role in the individual stages of preformulation studies for solid dosage forms. Examples are given to demonstrate this

The first stage involves chemical tests with the pure active substance using a reliable storage scheme. Then compatibility testing between active and inactive substances is performed. Under the general heading of sorption tests, the determination of sorption isotherms using special apparatus and their correlation with the physical and chemical changes which occur in the samples are discussed. With the results of these tests it is often possible to influence the sorption properties of the finished dosage form, for example by selection of the excipients and the salt form of the active substance, or by deferring the point of ansorption

Finally, as an example of special tests used in pre-formulation, the development of compound preparations is described and the galenical pre-stages are discussed     

Preformulation the Role of Moisture in Solid Dosage Forms

Abstract

Moisture plays an important role in the individual stages of preformulation studies for solid dosage forms. Examples are given to demonstrate this

The first stage involves chemical tests with the pure active substance using a reliable storage scheme. Then compatibility testing between active and inactive substances is performed. Under the general heading of sorption tests, the determination of sorption isotherms using special apparatus and their correlation with the physical and chemical changes which occur in the samples are discussed. With the results of these tests it is often possible to influence the sorption properties of the finished dosage form, for example by selection of the excipients and the salt form of the active substance, or by deferring the point of ansorption

Finally, as an example of special tests used in pre-formulation, the development of compound preparations is described and the galenical pre-stages are discussed     

Aging Effect on Stability and Eioavailability of Glibenclamide in Solid Dosage,Forms

Abstract

Asing effect of some solid dosage form of glibenclamide, after storage at various storage conditions and accelerated temperatures for certain length of time, affected percentage degradation, physical. properties, in-vitro dissclution and in- vivo performances, has been, investigated and compared with the marketed tablets of Dionil®. The percentage degradation responding to accelerated conditions has been extrapolated by formal Arrhenius treatment. Fowever, maximum stability and highest shelf-life of direct compression, lactose tablets, followed by Dionll^R and then suppositories have been observed. The aging and elevation of temperature, adversely affected dissolution rate and indicated a decrease In bioavailability of glibenclamide based on C_max, and T_max and AUC.     

Aging Effect on Stability and Eioavailability of Glibenclamide in Solid Dosage, Forms

Asing effect of some solid dosage form of glibenclamide, after storage at various storage conditions and accelerated temperatures for certain length of time, affected percentage degradation, physical. properties, in-vitro dissclution and in- vivo performances, has been, investigated and compared with the marketed tablets of Dionil®. The percentage degradation responding to accelerated conditions has been extrapolated by formal Arrhenius treatment. Fowever, maximum stability and highest shelf-life of direct compression, lactose tablets, followed by Dionll^R and then suppositories have been observed. The aging and elevation of temperature, adversely affected dissolution rate and indicated a decrease In bioavailability of glibenclamide based on C_max, and T_max and AUC.     

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.     

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.     

Preformulation Studies of Drug Substances for Solid Dosage Forms

Abstract

Azelastine hydrochloride, an investigational drug, was observed to form a hydrate or solvates upon recrystallization. X-ray diffraction and thermal analytical studies indicate that the hydrate or solvates exist in crystalline forms different from that of the parent material. Thermal analytical techniques confirmed that azelastine forms hydrate or solvates as opposed to a polymorph. The enthalpies and entropies of transitions were determined. A difference in dissolution rate of unrecrystallized and recrystallized azelastine was found.     

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.     

Effect of Particle Size and Excipients on the Dissolution Rate of Metronidazole from Solid Dosage Forms: II

In-vitro dissolution tests were carried out with tablets prepared from different particle size ranges of metronidazole. Influence of tablet binding agents (Methylcellulose, polyvinyl pyrrolidone - (PVP), potato starch and gelatin) on the drug release were investigated under similar conditions. Comprimates containing PVP and drug with particle size 1.75 μm (in lactose mixture) gave optimum results. These findings may open new ways of formulating a metronidazole tablet exhibiting improved drug - liberation, subsequently with a better bioavailability than the KUON^R-Tablet manufactured in Hungary.     

Effect of Particle Size and Excipients on the Dissolution Rate of Metronidazole from Solid Dosage Forms: I

The use of metronidazole in the treatment of Trichomoniasis, Giardiasis, Amoebiasis and infections caused by anaerobic microbes has been well established. This communication outlines efforts made to design a metronidazole formulation with better absorption properties than the “KLION-Tablet”, currently manufactured by the Chemical Works of Gedeon Richter Ltd., Budapest, A relatively low solubility of the drug in water, and improper selection of vehicles contribute to low dissolution rate, hence limiting the absorption. Particle size reduction and the incorporation of lactose in the finer aggregating powder, showed increased dissolution rate.     

Effect of Particle Size and Excipients on the Dissolution Rate of Metronidazole from Solid Dosage Forms: I

Abstract

The use of metronidazole in the treatment of Trichomoniasis, Giardiasis, Amoebiasis and infections caused by anaerobic microbes has been well established. This communication outlines efforts made to design a metronidazole formulation with better absorption properties than the “KLION-Tablet”, currently manufactured by the Chemical Works of Gedeon Richter Ltd., Budapest, A relatively low solubility of the drug in water, and improper selection of vehicles contribute to low dissolution rate, hence limiting the absorption. Particle size reduction and the incorporation of lactose in the finer aggregating powder, showed increased dissolution rate.     

Effect of Particle Size and Excipients on the Dissolution Rate of Metronidazole from Solid Dosage Forms: II

Abstract

In-vitro dissolution tests were carried out with tablets prepared from different particle size ranges of metronidazole. Influence of tablet binding agents (Methylcellulose, polyvinyl pyrrolidone - (PVP), potato starch and gelatin) on the drug release were investigated under similar conditions. Comprimates containing PVP and drug with particle size 1.75 μm (in lactose mixture) gave optimum results. These findings may open new ways of formulating a metronidazole tablet exhibiting improved drug - liberation, subsequently with a better bioavailability than the KUON^R-Tablet manufactured in Hungary.     

Effect of Moisture on Solid Dosage forms. can the Arrhenius Equation be used as a Predictor?

It is shown that for pure (organic) solids, the Arrhenius equation is valid, except it may be difficult to elucidate the rate controlling parameter andor the predominant mechanism. The two most predominant mechanisms are Prout-Tompkins and Bawn kinetics.

One aspects of kinetic investigations is to extrapolate so-called accelerated data (e.g. elevated temperature data), to other temperatures (e.g. room temperature). In such cases the Arrhenius equation is usually resorted to, but it is necessary, always, to establish the correct mechanism, extract from it the pertinent, rate-controlling parameters, and extrapolate these to room temperature. At times it is possible to obtain phenomenological parameters which can be extrapolated.

In cases where solids are stored in the presence of moisture there are several subdivisions (a) cases where the moisture is in excess (plain Leeson-Mattocks model of non-ionizing substance) (b) cases where some of the moisture present is “bound”, i.e. not free to react, (c) the case of less than molar ratios of moisture to drug, (d) the case of adsorbed moisture, (e) the case of drug hydrates/anhydrate pairs.     

Effect of Moisture on Solid Dosage forms. can the Arrhenius Equation be used as a Predictor?

Abstract

It is shown that for pure (organic) solids, the Arrhenius equation is valid, except it may be difficult to elucidate the rate controlling parameter andor the predominant mechanism. The two most predominant mechanisms are Prout-Tompkins and Bawn kinetics.

One aspects of kinetic investigations is to extrapolate so-called accelerated data (e.g. elevated temperature data), to other temperatures (e.g. room temperature). In such cases the Arrhenius equation is usually resorted to, but it is necessary, always, to establish the correct mechanism, extract from it the pertinent, rate-controlling parameters, and extrapolate these to room temperature. At times it is possible to obtain phenomenological parameters which can be extrapolated.

In cases where solids are stored in the presence of moisture there are several subdivisions (a) cases where the moisture is in excess (plain Leeson-Mattocks model of non-ionizing substance) (b) cases where some of the moisture present is “bound”, i.e. not free to react, (c) the case of less than molar ratios of moisture to drug, (d) the case of adsorbed moisture, (e) the case of drug hydrates/anhydrate pairs.     

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.     

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.     

Correlation of Dissolution-Dialysis Rates with Bioavailability of Nitrofurantoin Solid Dosage Forms

The correlation of in-vitro dissolution-dialysis rates of solid dosage forms with in-vivo bioavailability was investigated. Dissolution-dialysis measurements were made of 50mg and 100mg tablets and capsules of Nitrofurantoin commercial products. The samples used represented product lots whose bioavailability had been previously reported. The dissolution-dialysis medium used was pH 7.2 phosphate buffer. A cellulose dialysis membrane was used. A high degree of correlation was osbserved between apparent dialytic rate constant (K_app) of the drug and reported in-vivo bioavailability parameters for all 50mg tablets. But the 50mg capsule K_app value, measured under the same test conditions, was higher and did not correlate with the tablet data. However a value correlating with tablet data was obtained when the stirring speed was reduced from 100 RPM to 10 RPM. A satisfactory correlation was not obtained for the 100 mg dosage forms. This might be due to bladder drug saturation reported to occur at higher dose levels of Nitrofurantoin.