Should Magnesium Stearate be Assessed in the Formulation of Solid Dosage Forms by Weight or by Surface Area ?

Abstract

Three batches of magnesium stearate differing in morphology, particle size, bulk density and specific surface area were compared in the preparation of Pyrazinamide direct compression tablets. When the lubricants were used in the same amount they gave rise to tablets differing in hardness, disintegration and dissolution. When they were used in such amounts to develop equivalent lubricating areas, the final characteristics of the tablets were almost identical. A direct correlation was found between lubricating areas and ejection force.     

Gas chromatographic determination of oxazepam from tablets and micro capsules in urine

Abstract

Three new and two commercially available sugar matrices were comparatively evaluated for several fundamental properties of direct compression powder systems. These properties included: particle size distribution, powder flow (determined by a recording powder flow meter), bulk density and moisture content. The matrices studied were Dipac, Nutab, and California and Hawaiian (C & H) Products A, B, and C. These matrices were formulated into chewable ascorbic acid, multivitamin, and antacid tablets, and analyzed for: weight uniformity, thickness, diameter, hardness, disintegration, resistance to impact stress, friability, dissolution and effect due to aging.

The data obtained showed that the new products (C & H products) were comparable, and in some cases, even superior to the commercially available ones.     

Comparative Evaluation of Several Direct Compression Sugars

Abstract

Three new and two commercially available sugar matrices were comparatively evaluated for several fundamental properties of direct compression powder systems. These properties included: particle size distribution, powder flow (determined by a recording powder flow meter), bulk density and moisture content. The matrices studied were Dipac, Nutab, and California and Hawaiian (C & H) Products A, B, and C. These matrices were formulated in to chewable ascorbic acid, multivitamin, and antacid tablets, and analyzed for: weight uniformity, thickness, diameter, hardness, disintegration, resistance to impact stress, friability, dissolution and effect due to aging.

The data obtained showed that the new products (C & H products) were comparable, and in some cases, even superior to the commercially available ones.     

Effervescent Tablets of Ascorbic Acid. I. Physical Study of the Possible components to Be Used

Abstract

The stability of ascorbic acid effervescent tablets is substantially affected by moisture. Therefore the choice of suitable excipients is a very important step in the formulation study of this type of tablets. This work reviews the most common excipients used in effervescent preparations. They are characterized by microscopical observation and determination of particle size distribution, density, moisture, hygroscopicity, and electrostatics. Hygroscopicity is the most important property when choosing an excipient for an effervescent preparation. Therefore, two different methods for its determination have been used.     

Lubricant sensitivity in function of paddle movement in the forced feeder of a high-speed tablet press

Context: The negative impact of magnesium stearate (MgSt) on the hardness of tablets is a well-known phenomenon, but the influence of paddle movement in the forced feeder on the lubricant effect during tablet compression is often neglected.

Objective: The purpose of this research was to investigate the influence of paddle speed in the forced feeder on tablet tensile strength (TS).

Materials and methods: Mixtures of microcrystalline cellulose (MCC) and MgSt (0.5%) were blended using different methods (low & high shear). After blending, the formulations were compressed into tablets. All parameters of the tableting cycle were kept constant except the speed of the paddles in the forced feeder.

Results and discussion: The blending technique affected the sensitivity of the formulation to the paddle speed. The TS of pure MCC tablets did not change in function of paddle speed, while tablets prepared by low shear mixing became softer at higher paddle speed. The TS of tablets manufactured using the high-shear mixed blend was low and did not vary in function of paddle speed, suggesting that overlubrication already occurred during the initial blending step. Furthermore, analysis of the machine parameters allowed evaluation of the influence of the paddles on the flowability, initial packing, and compactability of the powder mixtures.

Conclusion: The results elucidated that during manufacturing of tablets using MgSt-containing blends care should not only be taken during the blending step prior to tableting, but also during the tableting process itself, as paddle speed can affect tablet TS, a critical quality attribute.     

Development of optimized self-nanoemulsifying lyophilized tablets (SNELTs) to improve finasteride clinical pharmacokinetic behavior

Objective: Preparation of an optimized finasteride (FSD) lyophilized tablets loaded with self-nanoemulsifying drug delivery system (SNEDDS).

Significance: Enhance FSD bioavailability in male pattern baldness and benign prostatic hyperplasia.

Methods: Two-step optimization was implemented to achieve the study goals. First; the mixture design was used to develop an optimized SNEDDS through which the effect of cosurfactant number of carbon atoms on SNEDDS particle size and thermodynamic stability has been tested. Second; the different tablet excipients have been used to develop an optimized self-nanoemulsifying lyophilized tablets (SNELTs). The prepared tablets have been fully characterized. Interaction among tablet components has been studied. Finally, FSD clinical pharmacokinetic has been investigated on human volunteers.

Results: Anise oil and tween 80 were selected as oily phase and surfactant, respectively while different aliphatic alcohols were studied as cosurfactants. Percentages of oil, surfactant, and cosurfactants were significantly affecting SNEDDS particle size. Increasing cosurfactant number of carbon atoms achieved smaller particle size and higher stability. The optimized SNEDDS was found to contain 10.3455, 45.8972, and 43.7573% of anise oil, tween 80, and butanol, respectively. Variations in FSD cumulative release and disintegration time, from the prepared tablets, were attributed to change in the percent of plasdone XL, Avicel and silica. No interaction among components was noticed. Clinical pharmacokinetics illustrated significant enhancement in the studied parameters from the optimized lyophilized tablets loaded with drug SNEDDS when compared to marketed FSD product.

Conclusion: Lyophilized tablets could be considered as a good alternative for conventional solid dosage forms especially when loaded with drug nanosystems.     

Mucoadhesive tablets for the vaginal delivery of progesterone: in vitro evaluation and pharmacokinetics/pharmacodynamics in female rabbits

Objective: To develop mucoadhesive tablets for the vaginal delivery of progesterone (P4) to overcome its low oral bioavailability resulting from drug hydrophobicity and extensive hepatic metabolism.

Methods: The tablets were prepared using mixtures of P4/Pluronic^® F-127 solid dispersion and different mucoadhesive polymers. The tablets physical properties, swelling index, mucoadhesion and drug release kinetics were evaluated. P4 pharmacokinetic and pharmacodynamic properties were evaluated in female rabbits and compared with vaginal micronized P4 tablets and intramuscular (IM) P4 injection, respectively.

Results: The tablets had satisfactory physical properties and their swelling, in vitro mucoadhesion force and ex vivo mucoadhesion time were dependent on tablet composition. Highest swelling index and mucoadhesion time were detected for tablets containing 20% chitosan-10% alginate mixture. Most tablets exhibited burst release (～25%) during the first 2?h but sustained the drug release for ～48?h. In vivo study showed that chitosan-alginate mucoadhesive tablets had ～2-fold higher P4 mean residence time (MRT) in the blood and 5-fold higher bioavailability compared with oral P4. Further, same tablets showed 2-fold higher myometrium thickness in rabbit uterus compared with IM P4 injection.

Conclusion: These results confirm the potential of these mucoadhesive vaginal tablets to enhance P4 efficacy and avoid the side effects associated with IM injection.     

Development of immediate release Rupatadine fumarate 10 mg tablets: A Quality by Design (QbD) approach

Abstract

Objective: The main objective of this research is to develop an immediate release Rupatadine fumarate 10?mg tablets formulation by direct compression, through a Quality by Design approach in Costa Rica.

Methods: According to a Quality by Design approach; Target Product Profile, Quality Target Product Profile, and the Critical Quality Attributes were defined. In the preformulation study, compatibility tests were carried out between the raw materials. The Critical Material Attributes were established using Quality Risk Management. Three formulation prototypes were prepared by direct compression and its Critical Process Parameters were defined. The analysis of the prototypes was realized in terms of organoleptic properties, identification, potency, content uniformity, dissolution, disintegration, friability and loss by drying.

Results: All the prototypes showed a white or slightly pink surface, potency between 90.0 –110.0 % of the labeling, an acceptance value for the content uniformity lower than the specification (AV < 15), the dissolved amount of active pharmaceutical ingredient was greater than 85.0 % at 30?minutes, friability less than 1.0 %, a disintegration time less than 15?minutes and moisture content less than 2.0 %.

Conclusions: The approaching of a Quality by Design model to the current development allowed to obtain satisfactory results in the three formulation prototypes. The excipients to be used can be lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, pregelatinized starch, magnesium stearate, stearic acid, and PVP K-30.     

The effect of moisture on the physical characteristics of ranitidine hydrochloride tablets prepared by different binders and techniques

Abstract

The effect of moisture on the physical properties of ranitidine hydrochloride tablets prepared by direct-compression and by wet-granulation method using PVP or EC as binders was studied. Tablets adsorped moisture at 50 and 75 % RH (relative humidity) but lost moisture at 30% RH. Except storage at 75% RH, however, tablet volumes did not change significantly during the test period. Moisture sorption caused a decrease in strength of tablets except low humidity (30% RH). Also, the disintegration time of tablets showed a decrease at all conditions except 30% RH. Furthermore, generally dissolution profiles of tablets prepared by direct-compression and by ethyl cellulose remained unchanged. Changes in the binder type in the tablet formulations changed the water uptake properties and also the physical properties of tablets. Directly-compressed tablets were much susceptible to change caused by humidity than tablets prepared by wet-granulation.     

Continuous low-dose feeding of highly active pharmaceutical ingredients in hot-melt extrusion

Context: Manufacturing solid low-dose pharmaceutical products has always the homogeneity challenge. In continuous manufacturing, there is the additional challenge of feeding active pharmaceutical ingredient (API) dry powder at low rates. This paper presents a method for feeding API particles into a continuous extrusion process using a suspension. The challenges for feeding and the product homogeneity are both addressed.

Objective: The objective of this study is to demonstrate the feasibility of manufacturing low-dose extrudates by feeding the API particles in a diluted anti-solvent suspension.

Materials and methods: Extrudates with an Ibuprofen content of 0.021% and 0.043% (w/w) were prepared by feeding a 0.9% w/w suspension of Ibuprofen particles into a Coperion extruder.

Results and discussion: The homogeneity (RSD) of extrudates was tested during a time span of 30?min and had values between 2% and 7%.

Conclusion: Feeding particles in an anti-solvent suspension offers a simple feeding option for API and minor components which yield products of desired homogeneity. The liquid feeding approach offers a simplified process with enhanced process control possibilities.     

Effect of Moisture on the Physical and Chemical Stability of Granulations and Tablets of the Angiotensin Converting Enzyme Inhibitor,Enalapril Maleate

Abstract

Granulations and tablets of enalapril maleate in a lactose matrix were stored in open petri dishes at a range of relative humidities and respective moisture uptakes measured, Extrapolation of the moisture uptake rates measured at the exaggerated humidities yielded a critical humidity, i.e. humidity where the moisture uptake rate is zero and, therefore, least detrimental to the product.

Enalapril maleate was reasonably stable at the storage conditions. The hardness of the tablets decreased at all humidities except when stored with silica-gel. The disintegration times were unaffected except at very high humidities. The dissolution profiles of the tablets remained unchanged.     

Random Multimode Optical Media: II. Statistical Analysis of the Fibre Diameter Variations

Abstract

We analyse the stochastic fluctuations of one of the optical fibre parameters: the core diameter. The diameter variations are treated as a process. The randomness, stationarity and ergodicity of this process are analysed. The correlation functions, spectral density functions and probability density functions are also presented.     

In-Vitro Release and In-Vivo Availability of Chloro-Quine Phosphate Formulated Suppositories

Abstract

Chloroquine phosphate suppositories were formulated using witepsol H15 as a model base. The physicomechanical properties of the prepared suppositories were studied. In-vitro drug release as well as in-vivo availability were determined and compared with those from commercial tablets containing the same dose of the drug (250 mg). In addition, the effect of pH of the different segments of GIT on the partition coefficient of the drug was tested

Results revealed that formulated suppositories exhibit good mechanical properties as well as high release characteristics. Volunteers received suppositories showed urine peak level after 2 hrs while with those administered the tablets the peak was reached after 3 hrs. The total amounts released were 60% and 48% from the administered dose in case of suppositories and tablets respectively. The higher bioavailability of the medicament after rectal therapy is explained on the basis of the partition coefficient data. The obtained values were 0.667, 0.941 and 5.333 at pH 1.2, 6.8 and 7.4 respectively. Volunteers used the formulated suppositories did not suffer from any GI irritation which is accompanying the oral administration of the drug. The proposed formula had no irritating effect on the rectum     

Moisture-Activated dry Granulation in a high Shear Mixer

Abstract

The applicability of a 25 litre high shear mixer for moisture-activated dry granulation was examined. Microcrystalline cellulose, potato starch or a mixture of 50% m/m of each was used as moisture absorbing material. The effects of water content, wet massing time, moisture absorbing material and dry mixing time on the size distribution, and the compressibility of the granulations were investigated. Tablets were compressed on a single punch press from all the granulations and on a rotary press from a few of the granulations.

It was shown that the physical properties of the tablets were primarily affected by the water content, the moisture absorbing material, and the compression force. Tablets with low mass variation, high crushing strength, low friability, and short disintegration time were achieved with both tablet presses by using a mixture of microcrystalline cellulose and potato starch as moisture absorbing material.     

The Effect of Moisture Sorption and Desorption on Furosemide Tablet Properties

Abstract

The effect of moisture sorption and desorption on the physical characteristics of furosemide tablet was studied at moderately elevated temperatures and different relative humidity conditions over 20 days. The rate of moisture sorption and desorption was founud to follow first order kifietics within first hours. Except ambient conditions (RT/Amb.RH), moisture sorption caused a decrease in hardness values of furosemide tablets. Also the disintegration times of hydrated tablets showed a remarkeable decrease. Changes in hardness and disintegration time were dependent on the amount of water sorbed into the tablets. These significant changes occured during the first days of the test and then became invariant. The variations in hardness and disintegration times of tablets were irreversible as demonstrated by desorption experiments.

Furthermore, except storage at high temperature and high relative humidity dissolution parameters of tablets were less affected by moisture sorption and desorption.     

Synthesis of Hydroxypropyl Methacrylate/Polysaccharide Graft Copolymers as Matrices for Controlled Release Tablets

ABSTRACT

Hydrophilic matrices are an interesting option when developing drug delivery systems. With this aim, hydroxypropyl methacrylate was grafted onto hydroxypropyl starch and hydroxypropyl cellulose substrates by following the Ce(IV) redox initiation method. Different amounts of ethyleneglycol dimethacrylate, 7 and 34 mol%, as the crosslinking monomer, were also added. The drying of grafted products was carried out by lyophilization, obtaining white powders. Reaction yields (percent grafting, grafting efficiency, etc.) and some physical characteristics of the powders (particle size, moisture uptake, density, morphology, etc.) were determined. These parameters indicate how useful these products may be as potential matrices for direct compressed tablets. In this light, the powder flowability and the binding properties of each copolymer were determined. The graft copolymers can be considered of great interest as direct compression excipients. Due to their different chemical structure and composition, they showed differences in viscoelastic properties that revealed an interesting range of possibilities for use in drug delivery formulations. Tablets formulated with conventional excipients were also tested. Dissolution tests of various tablets were carried out. In 12 hr, 60–80% of the model drugs was released.     

Co-crystallization for enhanced dissolution rate of bicalutamide: preparation and evaluation of rapidly disintegrating tablets

Objectives: Enhance the dissolution rate of bicalutamide via co-crystallization with sucralose (sweetener), with the aim to develop rapidly disintegrating tablets with subsequent prompt dissolution.

Significance: Bicalutamide is antiandrogenic agent for the treatment of prostate cancer but has low and variable oral bioavailability, mainly attributed to poor dissolution. Co-crystallization with benign excipients is promising for dissolution enhancement with the additive serving dual functions. The benefit will become greater if dissolution enhancement is associated with the development of orodispersible tablets which is suitable for elderly patients who are the most vulnerable for prostate cancer.

Methods: Bicalutamide was dissolved in acetone in the presence of increasing molar ratios of sucralose. The solvent was evaporated while mixing to deposit crystals that were subjected to wet co-grinding until drying. The developed solids were characterized using Fourier transform infrared spectroscopy, differential thermal analysis and X-ray diffraction in addition to monitoring bicalutamide dissolution.

Results: Instrumental analysis provided evidences for co-crystallization which was initiated at 1:1 molar ratio of bicalutamide to sucralose with complete co-crystallization at 1:4 molar ratio. The co-crystals provided faster bicalutamide dissolution compared with the unprocessed drug and that recrystalized from acetone in the absence of sucralose. The formulation containing bicalutamide with sucralose at 1:4 molar ratio was selected for tablet formulation into which superdisintegrants were included. The developed tablets exhibited flash disintegration with subsequent fast dissolution of bicalutamide.

Conclusions: The study introduced co-crystallization of bicalutamide with sucralose as an efficient tool to enhance the dissolution rate and to develop rapidly dissolving tablets for intraoral administration.     

Study of the Relationship Between the Initial Rate of Moisture Sorption/Desorption of Norfloxacin Tablets to the Total Moisture and Temperature of Surrounding Environment

Abstract

The relationship between absolute moisture content of air (expressed as pounds of water per pound of dry air) at 25°C and 40°C to the initial rate of moisture sorption/desorption of NORFLOXACIN tablets was studied. At the temperatures and relative humidities in the study, linear relationships were observed.

The initial rate of moisture sorption/desorption was found to be dependent upon both the moisture content as well as the temperature of the surrounding environment.     

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.     

Design and evaluation of mucoadhesive vaginal tablets of tenofovir disoproxil fumarate for pre-exposure prophylaxis of HIV

Objective: To design and evaluate novel, feasible, safe, mucoadhesive intravaginal tablets of tenofovir disoproxil fumarate (TDF).

Significance: It may provide pre-exposure prophylaxis for women against HIV.

Methods: TDF intravaginal tablets were formulated employing poylvinylpyrrolidone (PVP) as the matrix forming polymer and various mucoadhesive polymers such as carbopol 934, 940, chitosan, and sodium carboxymethylcellulose (SCMC). Wet granulation was used. The evaluation involved testing drug-excipient compatibility, precompression parameters such as percentage yield, bulk density and tapped density of the granules, Carr’s index, Hausner ratio, angle of repose, post compression parameters such as color, shape, physical dimensions, weight variation, hardness, friability, swelling index, assay, in vitro dissolution study and ex vivo mucoadhesion studies.

Results: Based on in vitro evaluation, C1 was selected as the best formulation and evaluated further for release kinetics, curve fitting analysis, absorption studies using liquid chromatography-mass spectrometry (LC-MS) technique and histopathological assessment in female Sprague–Dawley rats. C1 followed Higuchi model kinetics. Accelerated stability study was as per ICH guidelines by keeping C1 at 40?±?2?°C and 75?±?5% RH for six months.

Conclusions: C1 was selected as the best formulation due to better swelling index (65.93% at 24?h), prolonged release of 100.62% cumulative drug release (CDR) at 24?h, superior mucoadhesion force (35.93?×?10² dynes/cm²) and retention time (16?h). The study revealed that C1 remained stable for six months. C1 showed nil systemic absorption which is desirable and according to histopathological study, C1, exhibited minimal damage on the rat vaginal epithelium indicating safety.