Measurement of the Surface Area Changes During the Dissolution of Poorly Soluble Drugs using a Wide Angle Photosedimentometer

Using a Wide Angle Photosedimentometer, surface area changes during the dissolution of suspended particles of frusemide, glibenclamide and bendrofluazide have been measured. The method consisted of recording the change in optical density that occurs whilst the drugs are agitated in water in a 4cm square photosedimentometer cell. It was found that initially a high surface area was recorded which diminished exponentially with time and obeyed first order kinetics. From the surface area measurements, graphs of percentage drug dissolved against time were calculated and plotted and these profiles were found to correlate with similar plots of dissolution rate produced by analysing the amount dissolved spectrophotometrically. It was concluded that the surface area method offers an alternative technique for the measurement of the dissolution rate of poorly water soluble drugs, particularly when no adequate method exists for analysing the dissolved fraction.     

Comparison of Solid-Liquid and Liquid-Liquid Mass Transfer

Abstract

Mass transfer from solutions of m-acetotoluide, phenacetin and salicylamide into a stationary solvent, water, was studied. A sharp concentration jump was found at the leading solute front for all three liquid-liquid systmes. A comparison was made between the mass transferred in solid-liquid and liquid-liquid systems. The dissolution of m-acetotoluide, phenacetin and salicylamide was compared with mass transfer of solute from solutions with concentrations C_i, 2C_i and C_s into the pure solvent. In all cases, the amount dissolved from the solid was approximated by the C_i or the 2C_i-solvent system with the amount transferred in the C_s-solvent system approximately 100 fold greater than was dissolved from the solid. It was concluded that a concentration much less than saturation exists at the solid-liquid interface and that dissolution of the three compounds studied is controlled by the rate of solvent interaction at the solid surface.     

High Energy Ordered Mixture for Improving the Dissolution Rate of Sparingly Soluble Compounds

Abstract

Bioavailability of a sparingly soluble drug is often limited by the rate of dissolution of the drug substance. The drug in a micronized form is generally employed to maximize the bioavailability. However, the micronized drugs tend to agglomerates and do not always exhibit an improved dissolution rate. In this study, a simple processing using a high energy mill was demonstrated as an effective means to utilize the entire surface area available for drug release of the micronized drug. An experimental hydrophobic drug in a micronized form was milled with a carrier, hydrous lactose using Micropulverizer to achieve a uniform mixture so-called “high energy ordered mixture”. The high energy ordered mixture provided a contact surface area taking part in dissolution 4-fold greater than the micronized drug agglomerates. Therefore, the dissolution was significantly improved, irrespective of test parameters such as agitation and the presence of surfactant. This high energy ordered mixture provided the advantages over a simple ordered mixture for: (i) complete deaggregation of the micronized drug to fine primary particles, (ii) improving the efficiency of the carrier by increasing contact surface area, and (iii) enhancing the bonding effect between the drug and lactose particles due to free water molecules released from the crystal lattices of hydrous lactose during milling. This procedure could be applied to overcome dissolution problems of sparingly soluble drugs with cohesive nature.     

Etodolac-Liquid-Filled Dispersion into Hard Gelatin Capsules: An Approach to Improve Dissolution and Stability of Etodolac Formulation

ABSTRACT

The formation of melt dispersion is an effective method of increasing the dissolution rate of poorly soluble drugs, and hence, of improving the bioavailability. The carrier fusion method was used to prepare different dispersion of etodolac using Gelucire 44/14 and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). The physical characteristics of the binary systems were determined by differential scanning calorimetry (DSC), infrared spectroscopy (IR). The release rate from the resulting dispersion was determined from dissolution studies by use of USP dissolution apparatus II (paddle method). The dissolution rate of etodolac is increased in all the dispersion systems compared to that of pure drug. A liquid dispersion system of etodolac (20%) and Gelucire 44/14: TPGS blend (80%), in different ratios, was also prepared. The capsule formulation was subjected to stability studies at different temperature and humidity conditions as per ICH guidelines. Physical and chemical properties of the dispersion didn't change during a period of storage at room temperature and at 4°C, 0% RH. It was found that etodolac was chemically stable against the effects of temperature and humidity. However, the relative humidity and storage time exerted an effect on the dissolution behavior of etodolac. The changes in dissolution behavior after storage under conditions of high humidity and temperature might be related to the formation of etodolac microcrystal and to water absorption by the carrier during storage. It is predicted that acceptable shelf-lives should result when moisture-resistant packaging is used for pharmaceutical formulations of this type.     

Ehancement of Dissolution Rate by Incorporation into a Water Insoluble Polymer,Polycaprolactone

Abstract

This report concerns the use of water insoluble polymer, polycaprolactone, as a carrier to enhance the dissolution rate of two drugs, chlorpromazine and progesterone. Polycaprolactone microspheres containing these drugs were prepared by an emulsion-solvent evaporation technique and dissolution characteristics were compared to pure drug.

Dissolution studies revealed that both chlorpromazine-poly-caprolactone and progesterone–polycaprolactone microspheres exhibited a faster dissolution rate than the pure drugs. Molecular or colloidal dispersion of drugs in the polycaprolactone microshere matrix and the high permeability of polycaprolactone to the drugs and water are possible reasons for the rapid release perties observed.     

Role of Surfactant on Drug Release from Tablets

Abstract

The addition of a surfactanat into a tablet formulation appears to be attractive method of improve the drug release rate. The improved release rate is often associated with the effect of surfactant increasing the hydrophilicity of the dosage form thereby promoting drug dissolution. The findings of this investigation showed tha the presence of surfactant infulenced the tablet disintegration rate, producing a finer dispersion of disintergrated particles. It follows that the action of surfactant improving drug dissolution from tablets may be attributed ot the aciton of surfactnat producing fine disintegrated particles with correspondingly larger surface area for drug dissolution. It was also demonstrated that upon tablet disintergration the disinstegrated particles have a tri-moal frequency distribution.     

Dissolution of Some Lithium Dosage Forms and Correlation with Enslin Number

Abstract

The biopharmaceutic parameters of six conventional and one sustained release lithium carbonate commercial products were determined. From the dissolution data mean residence time, dissolution rate constants, and percent dissolved at 5 and 10 minutes were obtained. The ENSLIN numbers were compared with mean residence time and percent dissolved at 5 and 10 minutes. A good correlation was obtained between ENSLIN number and mean residence time for the conventional preparations.     

A Method of Coating Non-Uniform Granular Particles

Abstract

A method was developed for coating non-uniform granular particles In a uniform and controlled manner. Specific surface area was calculated based on the sieve-analysis data of uncoated theophylline granules which was used as the model compound. Theophylline granules were coated with different amounts of Eudraglt® L30D utilizing a Wurster coating apparatus. The in-vitro dissolution rate profiles of several batches were determined. Standard dissolution curves were established based on the amount of Eudraglt® L30D applied per unit area of theophylline granules. Using these curves as a standard, a prediction of dissolution rate could be made based on the knowledge of specific surface area of the theophylline granules and the amount of coating applied.     

Effect of Grinding of β-Cyclodextrin and Glibenclamide on Tablet Properties. Part I. in vitro

Abstract

Physical properties including dissolution characteristics of glibenclamide (GB) tablets were studied. Directly compressed and wet-granulated GB tablets gave only 35% and 40% drug dissolved, respectively. Physical mixing, kneading, and grinding of β-cyclodextrin (CD) with GB were investigated. It was found that the grinding method could markedly enhance the release of drug from the tablets. The physical properties of these tablets were unchanged after they had been stored at 40°C and 75% RH for at least 3 months. The GBKD mixture at a ratio of 1 to 4, ground for 24 or 48 hr, exhibited superior dissolution and chemical stability. Differential scanning calorimetry indicated that an inclusion complex was produced. Decreasing grinding time or CD concentration could result in incomplete formation of the inclusion complex. It was concluded that pretreatment of the drug with CD by the grinding method could significantly improve the dissolution and stability of GB tablets.     

A New Approach for Enhancing the Dissolution Rate of Phenacetin

Abstract

Numerous attempts are conducted so as to develop a rapid dissolution rate for those poorly water-soluble drugs. A new approach for enhancing the intrinsic dissolution rate of phenacetin is ascribed. This technique is based on the concept of the recrystallization of phencetin from different surfactants concentrations. The observed enhancing effect in the dissolution rate of phenacetin, using this technique, may be cue to wetting and/or deaggregation effect. The dissolution rate study was investigated in 0.1 N HC1 at 37°C and 50 r.p.m. The experimental study showed that the dissolution rate, during the first few minutes, is markedly affected by this technique. The relative area under the curve from 0 to 30 minutes (R.A.U.C.) was used as a parameter to 0–30 compare the different dissolution rates of the drug after being recrystallized from 1% w/v of each surfactant solution. The extent, in the dissolution rate enhancing effect, was found to range from 2.66 to 3.25 times of that of the control. This technique is valuable as a preformulation phase of phenacetin in solid dosage forms.     

Synchronized release of bufadienolides in a stable Lutrol F127 based solid dispersion prepared with spray congealing

Objective: The objective of this study was to design and prepare a novel solid dispersion using spray congealing to achieve fast and synchronous dissolution of bufalin, cinobufagin, and resibufogenin, three therapeutically complementary drugs.

Methods: The solid dispersion was characterized with dissolution, X-ray diffractometry, and fourier transform infrared spectroscopy after preparation and storage for four?weeks at different temperatures and relative humidity.

Results: It was found that all drugs were molecularly dispersed within matrix and had a significant enhancement (～4-fold higher) of dissolution rate. Furthermore, synchronized release of different drugs from a single carrier was achieved due to the highly molecular dispersibility and the excellent solubilization properties of F127. In addition, the solid dispersion was physically stable for at least four?weeks at controlled conditions. But for samples under stress conditions, the results showed that drug-rich phase was formed and storage temperature was the dominant factor in determining stability of the solid dispersion (SD).

Conclusions: These findings highlight the fitness of spray congealing to co-deliver multiple drugs, which open new perspectives for the development of more advanced combination of multiple therapeutic agents, presumably improving the bioavailability and therapeutic efficacy.     

Effect of Particle Size on the Dissolution Characteristics of Chlorthalidone

Abstract

The particle size reduction of chlorthalidone by fluid energy milling, Alpine milling and Fitzpatrick milling were evaluated. The desired particle size was achieved by both the fluid energy milling and Alpine milling processes. Alpine mil1ing, however, is a more complex process and is susceptible to product decomposition, whereas fluid energy milling is a simple and efficient process without any risk of product decomposition. The desired particle size cannot be achieved by Fitzmilling because of the low probability of impaction force on particles. The dissolution rate of the chlorthalidone from chlorthalidone/propranolol hydrochloride tablets (25/80 mg) prepared with fluid energy milled chlorthalidone was significantly better than the tablets prepared with Fitzpatrick - milled chlorthalidone. The minimum effective specific surface area of chlorthalidone needed for maximum dissolution in water was found to be around 3.5 m²/g.     

Soft Gelatin Capsules Iii: An Accelerated Method for Evaluating the Dissolution Stability of Various Gel Formulations

Abstract

A rapid method has been developed for the evaluation of the dissolution stability of various preformulation gels. Freshly prepared gel samples, after proper drying, were stored over a drying agent at above room temperatures. Periodically the dissolution of a stability sample in % dissolved for a given time was determined spectrophotometrically. In this manner, various preformulation gels could be evaluated in a relatively short time by changes in their dissolution rates from a slope values versus time plot for a given storage condition. Other applications of the method were in screening various plasticizers and additives for their solubility enhancing or protective properties.     

Aquesons Films Coating Stuied of Sustabined Release Niciotine Acid Fellets: An In-Vitro Evalutiion

Abstract

Numerous batches of nicotinic acid (niacin) pellets were coated to determine the optimum level of Surelease® coating which would exhibit in-vitro release patterns suitable for BID dosing. Various levels of Surelease, with and without the incorporation of a hydrophilic material, were studied. It was expected that a significantly high level of Surelease would be needed to obtain the desired in-vitro dissolution release rate for the water soluble drug. However, a coating level of 1.2% Surelease coating was found to have an in-vitro dissolution profile approximating that of a BID product. Scanning electron microscopic examination has shown that the surface of coating is smooth and uniform with the coating thickness of about 2 μm. The 2 months stability data showed no significant changes in the dissolution profiles.     

The Effect of Selected Water-Soluble Excipients on the Dissolution of Paracetamol and Ibuprofen

The purpose of this investigation was to study the dissolution behavior of paracetamol and ibuprofen in the presence of a range of selected potential excipients. First, a pH-solubility profile was generated for both drugs, and the effect of changing hydrodynamic conditions on the intrinsic dissolution rate was investigated. It was established that both drugs dissolved according to the diffusion-layer model. Paracetamol solubility (approximately 20.3 mg mL^{? 1}) did not vary from pH 1.2–8.0, corresponding to the in vivo range in the gastrointestinal tract. Ibuprofen had an intrinsic solubility of approximately 0.06 mg mL^{? 1}, and pK_a was calculated as 4.4. Second, the effects of selected potential excipients (lactose, potassium bicarbonate, sodium bicarbonate, sodium chloride, and tartaric acid) were evaluated by measuring the effect of the inclusion of each additive in the dissolution medium on drug solubility, drug intrinsic dissolution rate, and solution viscosity. The results were evaluated using the diffusion-layer model, and it was determined that for paracetamol, the collected data fitted the model for all the excipients studied. For ibuprofen, it was found that there were differences between the excipients that raised the solution pH above the pK_a to those that did not. For the excipients raising the pH above the pK_a, the effect on intrinsic dissolution rate was not as high as that expected from the change in drug solubility. It was postulated that this might be due to lack of penetration of the excipient into the drug boundary layer microenvironment. Formulators may calculate the effect of adding an excipient based on solubility increases but may not find the dissolution rate improvement expected.     

The Effect of Mixing Variables on the Dissolution Properties of Direct Compression Formulations of Furosemide

Abstract

The particles of a number of poorly water soluble drugs, for instance furosemide, tend to agglonierate spontaneously and as a result decrease the drug's dissolution properties. This phenomena is undesirable when the drug is to be formulated in a direct compressible formulation. Interactive or ordered mixing with a filler usually rectifies this problem but the drug load is limited to a maxirnuni of ± 5% of the mixture. This is well below the formulation requirements of hrosemide (25 %) and below the maximum drug load which can be handled in dircct compression formulations (± 35 %). The effect of two types of mixers, the mixing time and drug load were investigated for a direct compression formulation of furosemide tablets. A Turbula and a V mixer, both with a volume of 720 ml, were used. The drug was formulated with Ludipress (a commercial direct compression filler, BASF, Germany) at two drug loadings of 20 and 25 %. Magnesium stearate (1 %) was added as a lubricant. A mixture was prepared for each experimental condition. After mixing the whole mixture (120 gram) was tabletted on a Korsch single punch machine producing ± 500 tablets. The crushing strength, mass and disintegration time of ten tablets and the dissolution of six tablets were measured. Dissolutions were donc according to the USP XXII - method 2¹ - in 0, 1 M HCI and a phosphate buffer with pH = 5.8. The intrinsic dissolution rates of some of the mixtures were also deterniined in the two dissolution media. The dissolution properties of the formulations were compared with the properties of Lasix®, a commercially available furoseniide product. which is not manufactured by dircct compression. The dissolution rates of the formulations mixed in the Turbula mixer were significantly higher than those mixed in the V miser. The area under the dissolution curves increased as a function of niixing time for both mixers. The best dissolution results were obtained for formulations with a 20 % drug load and mixed for 120 minutes in the Turbula miser. The dissolution curves for these formulations compared well with the curves for the commercial tablets. Intrinsic dissolution rates were also a hnction of niising time, which indicates that the increase in dissolution properties is probably a result of the deagglomeration of the agglomerated furosemide particles. The Turbula mixer, which can develop more shear force, breaks the agglomerates quicker and to a larger extend than the V mixer. It can be concluded that the type of mixer, mixing time and drug load control the dissolution properties of direct compression formulations of poorly water soluble drugs in which the drug particles form agglomerates.     

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.     

Dissolution Rate of Polymorphs and Two New Pseudopolymorphs of Sulindac

Abstract

This study reports the enhancement of sulindac dissolution rate by using the acetone and chloroform solvated forms. me intrinsic dissolution rates of potymorphs I and II and the influence of crystal habit on the drug dissolution process have also been studied. The dissolution properties were studied by calculating the intrinsic dissolution rate (k) by linear regression analysis from the amount dissolved versus time. The results indicated that the intrinsic dissolution rates of solvates in acetone and chloroform were much higher (k = 0.076 mg min^?1cm-², respectively) than those of polymorphs I and II (k = 0.036 mg min^?1cm^?2). However, the dissolution rates of the two solvates were found to be essentially the same and independent of the solvent nature. The intrinsic dissolution rates of form II recrystal-lized in methanol and ethanol differed (k = 0.031 and 0.036 mg min^?1cm^?2, respectively), which confirms the influence of crystal habit on sulindac dissolution rate. No significant difference in dissolution profiles were observed between forms I and II, in agreement with the similar values of fusion cemperature (1187 and 183°C respectively.     

Physicochemical Characterization of L-691, 121, a Potent and Selective Class III Antiarrhythmic Agent

Abstract

The physicochemical properties of the novel antiarrhythmic agent L-691, 121 [methanesulfonamide, N- (1′- (2- (5-benzofirazanyl)ethyl)-3, 4-dihydro-4-oxospiro(2H-1-benzopyran-2, 4′-piperdin)6-yl), hydrochloride] have been studied, with particular emphasis on the stability, solubility, and dissolution properties of the drug. Solubility data in the pH range 0.5 to 11 show several distinct regions which are consistent with the existence of dicationic, cationic, neutral, and anionic forms of the drug. Dissolution studies were carried out using a continuous flow system which employed a conductance flow cell to monitor dissolved drug concentration. It is shown that the surface area of the drug is an important property in determining the dissolution rate. Solution stability studies indicate that the drug is prone to undergo a base-catalyzed elimination reaction which produces an N-dealkylated product. The preformulation data are used to develop intravenous and oral dosage forms suitable for clinical use.     

Miconazole and Miconazolenitrate Chewing Gun as Drug Delivery Systems – A Practical Application of Solid Dispersion Technique

Abstract

Miconazole and miconazolenitrate are antifungal drugs with poor solubilities in water and saliva. The low solubilities meant that only small amounts of the drugs – incorporated by a conventional method in chewing gum-were released during mastication. The experiments were performed on a mastication device.

In this study it was shown that application of a 20% miconazole – 80% polyethyleneglycol 6000 solid dispersion drastically improved the in vitro release of miconazole from cheving gum, when a medium similar to saliva was used. In addition to polyethyleneglycol 6000, polyvinylpyrrolidone 40000, xylitol and urea were tested as carriers. It was also shown that the release rate of miconazole from chewing gum was much greater than the release rate of miconazolenitrate.

No certain correlation could be shown between the dissolution rates of the solid dispersions measured by a stirring paddle method and the release rates of miconazole from solid dispersions in chewing gum.

The solid dispersion systems were characterized by differential scanning calorimetry. The systems containing polyethyleneglycol 6000 and xylitol were eutectic. Polyvinylpyrrolidone 40000 prevented crystallisation of miconazole when the percentage of drug in the solid dispersion was less than 50%.