Effect of Excipient and Processing Variables on Adhesive Properties and Release Profile of Pentoxifylline From Mucoadhesive Tablets

ABSTRACT

The bioavailability and onset of action of drugs with high first-pass metabolism can be significantly improved by administration via the sublingual route. The objective of this study was to evaluate the effect of polymer type and tablet compaction parameters on the adhesive properties and drug release profile from mucoadhesive sublingual tablet formulations. Pentoxifylline was selected as the model drug because it has poor oral bioavailability due to extensive first-pass metabolism. Two polymers known to possess mucoadhesive properties, carbomer and hydroxypropyl methyl cellulose (HPMC), were used to prepare the formulations. Tablets were prepared by using direct compression technique and evaluated for in vitro dissolution, drug-excipient interactions, and adhesive properties. In general, there was a decrease in the rate of drug release with an increase in the concentration of polymers. No drug-excipient interactions were evident from differential scanning calorimetry or high-performance liquid chromatography analysis. For the formulations containing HPMC, the force of mucoadhesion increased with an increase in the concentration of polymer; however, for carbomer formulations, no such correlation was observed. Force of mucoadhesion decreased as a function of hydration time in both of the polymers.     

Effect of lyophilized grapefruit juice on P-glycoprotein-mediated drug transport in-vitro and in-vivo

The administration of grapefruit juice (GFJ) has been postulated to inhibit the activity of P-glycoprotein (P-gp) transport system and thus can enhance the uptake of substrate drugs. However, for various reasons, the results obtained have been always swaying between confirmation and refutation. This study aims at re-evaluating the effect of lyophilized freshly-prepared grapefruit juice (LGFJ) prepared from the whole peeled fruit on P-gp activity using the model drug doxorubicin (DOX) in-vitro and timolol maleate (TM) in-vivo. Human uterine sarcoma MES-SA/DX5v cells, grown under nanomolar concentration of DOX and highly expressing P-gp, were used as model cells for in-vitro studies whereas white New Zealand male rabbits were used for in-vivo studies. Results showed that the accumulation of DOX in MES-SA/DX5v cells was increased by 18.3?±?2.0% in presence of LGFJ compared to control experiments. Results from in-vivo absorption studies showed that the relative oral bioavailability of TM ingested with LGFJ was significantly higher by 70% and 43% compared to the oral bioavailability of TM ingested with saline and a commercial GFJ, respectively. This study as such confirms the inhibitory effects of LGFJ on P-gp efflux proteins and highlights the superiority of using lyophilized freshly prepared juices over the commercially available juices in research studies. Also, the results call for further studies to assess the possibility of co-administrating LGFJ with anti-cancer agents to modulate multidrug resistance in their cellular environment or incorporating LGFJ in solid dosage forms to improve oral bioavailability of drugs.     

The Effect of Four Tablet Binders on the Bioavailability of Frusemide from 40MG Tablets

Tablets containing frusemide 40mg have been prepared using four different binders; polyvinylpyrrolidone, starch mucilage, stearic acid and methylhydroxyethyl cellulose. With the exception of the tablets prepared using stearic acid, all the tablets disintegrated in under 2 minutes and exhibited hardnesses ranging from 12 to 17 s.c.u. The dissolution rate, measured in the B.P. apparatus as the time to achieve 50% solution in distilled water, discriminated more effectively between the tablet batches. Tablets made using polyvinylpyrrolidone and methylhydroxyethyl cellulose had dissolution half lives of 3.65 and 3.30 minutes respectively, whilst tablets incorporating stearic acid and starch mucilage exhibited respective values of greater than 200 minutes and 117 minutes. The bioavailabilities of the four tablet formulations were assessed on a double blind basis in four healthy males aged 18-30 with reference to an oral frusemide solution. The bioavailability of each formulation was determined by two different methods and it was found that polyvinylpyrrolidone and methylhydroxyethyl cellulose rendered frusemide equally bioavailable (71.7% and 71.6% respectively) whilst the starch mucilage formulation rendered frusemide 25% less bioavailable (54.10%). The poorest binding agent was stearic acid which decreased the bioavailability of frusemide by 50% (35.04%). The results indicate that the choice of binding agent can significantly affect the bioavailability of frusemide from tablets and that these bioavailability differences can best be detected in vitro by dissolution rate measurements.     

The Effect of Lubricants on the Properties of Chloroquine Phosphate Tablets

Abstract

The properties of tablets prepared from different size fractions of chloroquine phosphate granules using different lubricants were evaluated. Lubricants used were magnesium stearate, stearic acid and talc, tablet properties studied include weight variation, crushing strength, friability and disintegration time

The effects obtained were largely dependent on the type and concentration of lubricant. Generally, as granule size increased, tablets were found to show increased weight variation, decreased hardness and increased friability. With tablets containing talc as lubricant, disintegration time was shown to decrease with increase in granule size.

There appears to be an optimum lubricant concentration for the compression of different granule size fractions.     

Effect of Crospovidone on the Physical Properties of Acetaminophen Tablets

Acetaminophen tablets containing minimum amount of excipients and varying amounts of cross linked polyvinyl pyrrolidone were prepared under accurately controlled conditions of compression speed and pressure. The disintegration time, dissolution rate, crushing force, friability as well as effect of temperature and humidity on these parameters during storage were determined. Increasing proportions of the cross linked polymer (1-10%) did not influence crushing force or friability but significantly decreased disintegration and dissolution time. Satishctory tablets with desired properties were obtained by incorporation of optimum quantity of crospovidone. Storage of acetaminophen tablets at room temperature and humidity for a period of 4 weeks did not alter any of the physical properties tested weekly. However the combined effect of elevated temperature and humidity on tablet properties, especially on the dissolution time was significant. The influence of incorporation of equal amounts of crospovidone intragranularly and intra-plus extragranularly on the properties of granules and tablets were also evaluated with scaled-up formulations.     

Effect of Crospovidone on the Physical Properties of Acetaminophen Tablets

Abstract

Acetaminophen tablets containing minimum amount of excipients and varying amounts of cross linked polyvinyl pyrrolidone were prepared under accurately controlled conditions of compression speed and pressure. The disintegration time, dissolution rate, crushing force, friability as well as effect of temperature and humidity on these parameters during storage were determined. Increasing proportions of the cross linked polymer (1-10%) did not influence crushing force or friability but significantly decreased disintegration and dissolution time. Satishctory tablets with desired properties were obtained by incorporation of optimum quantity of crospovidone. Storage of acetaminophen tablets at room temperature and humidity for a period of 4 weeks did not alter any of the physical properties tested weekly. However the combined effect of elevated temperature and humidity on tablet properties, especially on the dissolution time was significant. The influence of incorporation of equal amounts of crospovidone intragranularly and intra-plus extragranularly on the properties of granules and tablets were also evaluated with scaled-up formulations.     

Effect of Drug Solubility in Wet Granulation Fluids on the Dissolution Rates of the Resulting Tablets

One factor in wet granulation processes which affects dissolution rates of the final tablets is shown to be the solubility of the drug substance in the granulating liquid. The relationship is not a direct correlation and a feasible explanation is offered.     

The Effect of the Variability in the Physical and Chemical Properties of Magnesium Stearate on the Properties of Compressed Tablets

Abstract

A series of magnesium stearate samples, supplied by foreign and domestic manufacturers, were characterized by their physical and chemical properties. The results Indicated that the samples differed significantly with respect to chemical purity, particle size and surface area. The properties of magnesium stearate lots, manufactured by the same company, were very similar. Whatever variation that was seen was principally due to different suppliers.

Microcrystall1ne cellulose tablet formulations were prepared and evaluated using samples of magnesium stearate obtained from 16 sources. Differences 1n tablet quality were observed 1n regard to bulk volume of the blends, tablet tensile strength, and tablet friability. The data revealed that the smaller particle sized magnesium stearate samples (2.4–7.0 μm), with a large surface area (10.6–14.8 m2/g), had the most detrimental effects on the physical properties of mlcrocrystalHne cellulose tablets. Regression analysis and modeling was used to define quantltate, and predict the effects of magnesium stearate source variation on the physical properties of mlcrocrystalHne cellulose blends and compressed tablets.     

The Effect of the Variability in the Physical and Chemical Properties of Magnesium Stearate on the Properties of Compressed Tablets

A series of magnesium stearate samples, supplied by foreign and domestic manufacturers, were characterized by their physical and chemical properties. The results Indicated that the samples differed significantly with respect to chemical purity, particle size and surface area. The properties of magnesium stearate lots, manufactured by the same company, were very similar. Whatever variation that was seen was principally due to different suppliers.

Microcrystall1ne cellulose tablet formulations were prepared and evaluated using samples of magnesium stearate obtained from 16 sources. Differences 1n tablet quality were observed 1n regard to bulk volume of the blends, tablet tensile strength, and tablet friability. The data revealed that the smaller particle sized magnesium stearate samples (2.4-7.0 μm), with a large surface area (10.6-14.8 m2/g), had the most detrimental effects on the physical properties of mlcrocrystalHne cellulose tablets. Regression analysis and modeling was used to define quantltate, and predict the effects of magnesium stearate source variation on the physical properties of mlcrocrystalHne cellulose blends and compressed tablets.     

The Effect of Some Surfactants on the in- Vitro Properties of Double Compressed Tablets

The effect of different types and concentrations of some surface active agents as well as the method of surfactant incorporation on the in - vitro properties of aspirin tablets as a model for double compressed tablets was studied. The formulated tablets were evaluated using the U. S. P. official tests and some other selected non-official tests. These tests include: uniformity of weight, uniformity of content, disintegration, dissolution, hardness, friability and thickness. Incorporation of a low concentration (0.2 % w/w) of surface active agents i n the formulation of tablets decreased the disintegration time but did not affect their dissolution rate. Higher concentrations of surface active agents retarded the dissolutiono of tablets. Non ionic surfactants showed higher regarding effect than ionic surfactants . Changing the method of surfactant incorporation did not greatly affect the dissolution rate of tablets.     

The Effect of Some Surfactants on the in- Vitro Properties of Double Compressed Tablets

Abstract

The effect of different types and concentrations of some surface active agents as well as the method of surfactant incorporation on the in - vitro properties of aspirin tablets as a model for double compressed tablets was studied. The formulated tablets were evaluated using the U. S. P. official tests and some other selected non-official tests. These tests include: uniformity of weight, uniformity of content, disintegration, dissolution, hardness, friability and thickness. Incorporation of a low concentration (0.2 % w/w) of surface active agents i n the formulation of tablets decreased the disintegration time but did not affect their dissolution rate. Higher concentrations of surface active agents retarded the dissolutiono of tablets. Non ionic surfactants showed higher regarding effect than ionic surfactants. Changing the method of surfactant incorporation did not greatly affect the dissolution rate of tablets.     

The Effect of Partice and Power Proterties on the Mechnical Properties of Directly Compressed Cellulose Tablets

The inherent material properties of four cellulose powers were evaluated and the effect of these properties on the mechnical strenght and surface hardness of direct compression tablest was studied. Two of the materials studied were the other two were experimental cellulose powers, and agglomerated cellulose and a deploymerized cellulose.

The agglomerated cellulose powder formed the strongest as well as the hardest tablets. Also both microcrystalline celluloses formed clearly stronger tablets than depolymerized cellulose, but surface hardness of the tablets compressed using these three cellulose powders was, however, quits similar.

The most important material property affecting the breaking strength of tablets was the suesific surface area of the starting material. No correlaiton between cystallinity, particle size or particule shape starting material and the strength of tablets was observed.

The surface hardness of tablets showed no simple correlation with the breaking strenth of tablets or with any single material property of cellulose powders. It is obvious, compacion could affect markeldy the hardbness of the compact surface, thus possibly masking the effect of a single material property.     

Effect of Crystallization of Theophylline on Physical Properties of Tablets

Tablets containing anhydrous theophylline, a hygroscopic material such as magnesium chloride or potassium acetate, and other constituents were stored for 4 and 12 weeks under 90% relative humidity at 37°C. During storage, whisker-like crystals appeared on the surface of the tablets. The crystals were observed under a scanning electron microscope. Changes were found in the physical properties of these tablets: crushing strength, friability, disintegration time and dissolution rate.     

Effect of Crystallization of Theophylline on Physical Properties of Tablets

Abstract

Tablets containing anhydrous theophylline, a hygroscopic material such as magnesium chloride or potassium acetate, and other constituents were stored for 4 and 12 weeks under 90% relative humidity at 37°C. During storage, whisker-like crystals appeared on the surface of the tablets. The crystals were observed under a scanning electron microscope. Changes were found in the physical properties of these tablets: crushing strength, friability, disintegration time and dissolution rate.     

Effect of Sodium Bicarbonate on the Properties of Metronidazole Floating Matrix Tablets

The effect of sodium bicarbonate (SB) on the swelling behavior and the sustained release of floating systems was studied with varied proportions of this excipient and metronidazole. Two polymers with different hydration characteristics, Methocel K4M and Carbopol 971P NF, were used to formulate the matrices. Under in vitro dissolution conditions, the addition of SB to metronidazole sustained-release tablets modifies the matrix hydration volume, increasing at the beginning, reaching a maximum, and then declining. Pure Carbopol matrices show a rapid hydration with a limited further effect of the SB and metronidazole loads. Methocel show a significant increase of the apparent hydration volume due to SB addition with no further notable change due to metronidazole load. Increasing the metronidazole load reduces the floating time of Carbopol matrices while no effect on Methocel matrices could be observed within 8 hours dissolution. Matrices show increasing release constant values (k) as the metronidazole load increases. Methocel matrices release the drug 10% to 15% faster than Carbopol matrices. SB increases the cumulative amount of drug released from Methocel but not that releasing from Carbopol. These results are attributed to the intrinsic polymer properties, the barrier effect of CO₂ bubbles, and the matrix volume expansion produced after addition of SB.     

Effect of Re-Conpression on the Properties of Tablets Prepared by Dry Granulation

The effect of re-compression on the tableting properties of some direct compression excipients (directly compressible starch, dicalcium phosphate dihydrate and microcrystalline cellulose) and their formulations was examined. Re-compression generally reduced the tablet strength and this reduction was more significant when the initial compaction was carried out at a higher pressure. The reason for the reduction of tensile strength upon re-working is attributed to work hardening and the production of robust granules, which have increased resistance to deformation compared to unworked granules.

This paper is based on a presentation made to the 31st National meeting of the Academy of Pharmaceutical Sciences, American Pharmaceutical Association, held at Orlando, Florida, U.S.A. on November 15-19th, 1981.     

Effect of Re-Compression on the Properties of Tablets Prepared by Moist Granulation

The effect of re-compression on the properties of tablets prepared by moist granulation using various binding agents was examined. The results show that re-working by dry granulation and re-compression (i.e. a slugging process) caused a reduction in tablet strength, which was related to the initial compaction pressure. This loss of compressibility was attributed to work hardening of granules during the compaction process. However, when compacts were milled, re-wetted and then re-compressed, the tablets produced were of similar strength to those obtained on initial compaction. Re-wetting reversed the effect of work hardening by reactivating the binder to produce granules more porous than those obtained by dry granulation.

This paper is based on a presentation made to the 31st National meeting of the Academy of Pharmaceutical Sciences, American Pharmaceutical Association, held at Orlando, Florida, U.S.A. on November 15-19th, 1981.     

The Effect of Aging on Disintegrant Efficiency in Direct Compression Tablets with Varied Solubility and Hygroscopicity, in Terms of Dissolution

The effect of tablet aging on the dissolution efficiency of three “super disintegrants”, sodium starch glycolate, crospovidone, and croscarmellose sodium, was investigated utilizing directly compressed tablets. Lactose, dicalcium phosphate dihydrate, and sorbitol, alone or in combination, provided varying degrees of solubility and hygroscopicity to the direct compression tablet formulations. The results indicate that aging did not decrease the effectiveness of the super disintegrants in promoting invitro dissolution. The composite solubility and hygroscopicity of the tablets did not adversely influence the aging characteristics of the super disintegrants. Super disintegrants that complied with the same compendial specifications but were obtained from different sources behaved similarly in promoting tablet dissolution after storage.     

Effect of Storage Conditions on The Physical Properties and In Vitro Dissolution of Directly Compressed Tablets

Abstract

Tablets of aspirin, ascorbic acid and pyridoxine hydrochloride were prepared by direct compression, using bone powder or Emcompress, respectively as direct compression fillers. Tablet properties such as mean weight, thickness, breaking strength and friability were monitored before and after storage for 30 days under specified temperature and relative humidity conditions. The tablet properties were apparently unaffected by the conditions of storage, while release parameters were, however, modified. In vitro dissolution rate constant, was found to exhibit good correlation with the dissolution efficiency.     

Effect of Storage Conditions on The Physical Properties and In Vitro Dissolution of Directly Compressed Tablets

Tablets of aspirin, ascorbic acid and pyridoxine hydrochloride were prepared by direct compression, using bone powder or Emcompress, respectively as direct compression fillers. Tablet properties such as mean weight, thickness, breaking strength and friability were monitored before and after storage for 30 days under specified temperature and relative humidity conditions. The tablet properties were apparently unaffected by the conditions of storage, while release parameters were, however, modified. In vitro dissolution rate constant, was found to exhibit good correlation with the dissolution efficiency.