Directly Compressible Acetaminophen Compositions Prepared by Fluidized-Bed Granulation

Polyvinylpyrrolidone (PVP) in aqueous solution was used as a binding agent in a fluidized-bed system to agglomerate acetaminophen powder into directly compressible granules. It was found that a minimal amount of 5% w/w PVP in a concentration of 7.5% w/v or less was needed to produce granules with an acceptable flow and the corresponding tablets having enough hardness without capping. There was a strong correlation between the time for 80% dissolved (T₈₀) and the logarithm of granule volume-surface mean diameter. A directly compressible acetaminophen composition to manufacture tablets having a T₈₀ value less than 30 min can be prepared simply by adding an appropriate amount of disintegrant (crospovidone, sodium starch glycolate, or pregelatinized starch) to the agglomerated granules.     

Fluidized-Bed agglomeration of acetaminophen; direct compression of tablets and physiologic availability

A novel process was developed for manufacturing acetaminophen in a free-flowing, directly compressible agglomerated form, involving spray agglomeration of acetaminophen powder with polyvinylpyrrolidone (PVP) in isopropyl alcohol as a bonding agent using a fluidized-bed granulator. Agglomerates prepared with 5% PVP yielded a free-flowing and compressible material. Upon lubrication with 0.5% magnesium stearate, the material was found to be directly compressible into tablets. To improve dissolution and tableting properties, the agglomerates were compressed into tablets after blending with varying weight ratios of microcrystalline cellulose/pregelatinized starch as a filler/disintegrant combination. The final stable tablet formulation consisted of agglomerates equivalent to 325 mg of acetaminophen, 2.1 mg of magnesium stearate, and the filler/disintegrant in a weight ratio of 70:30 to yield a tablet weight of 425 mg. Physical properties and dissolution profile of these tablets were comparable to those of a commercial acetaminophen tablet. Physiologic availability calculated using the urinary excretion method indicated half-lives of 2.0, 2.1, and 2.2 hours for control (acetaminophen powder), experimental tablet, and a marketed product, respectively.     

Effects of Temperature,Humidity, and Aging on the Disintegration and Dissolution of Acetaminophen Tablets

Abstract

The effect of storage for 8 weeks at 40°C in moderate and high humidity on acetaminophen tablets prepared by the wet granulation method using povidone or pregelatinized starch as a binder was studies. Storage at 52% relative humidity produced an increase in hardness of acetaminophen tablets and storage at 94% relative humidity caused a decrease in hardness. In all cases tablets granulated with pregelatinized starch were less susceptible to change caused by humidity than tablets granulated with povidone. The disintegration of tablets containing starch or povidone was slowed as the humidity was increased. Tablets stored at 40 =C and 94 V. relative humidity showed a substantial slowing of dissolution, but there was little change of dissolution of tablets when aged at 40 -C / 52% relative humidity. In comparing starch and povidone as binders, acetaminophen tablets prepared with pregelatinized starch were less effected by high humidity than tablets prepared with povidone.     

Evaluation of Binder Activities on the Physical Properties and Compression Characteristics of Granules Prepared by Two Different Modes

Abstract

The effects of various binders and binder concentrations in production of granules by two different granulation modes were first investigated on the basis of the granule size distribution. Increasing the amount of binder produced larger and less friable granules associated with a decrease in flow rate and an increase in angle of repose. The strength of granules prepared by either the wet conventional or the fluidized bed was a function of its mean particle diameter and of binder-content with the later factor being more predominant. The inclusion of paracetamol into the placebo formula decreased the granule crushing strength. The effect was more pronounced with smaller granules and decreased with increasing granule size.

The rank order of the paracetamol-PVP granules crushing strength was reversed for the tensile strength of their corresponding tablets, viz., the paracetamol-PVP tablets prepared from fluidized granulation exhibited a higher tensile strength than that compressed from wet granules. A new parameter index “ø_b index” which combines tablet characteristics is presented. The index proposed allowed an overall simpler quantitative evaluation of a binder activity. Incorporated into this index are four tablet parameters, viz., tensile strength, percent porosity, median dissolution time, and percent friability. A higher “ø_b, index” infers better physical properties of tablets. Binders used in this study are then classified according to this index: PVP > gelatin > PEG 6000.     

Preparation of medicinal carbon tablets by modified wet compression method

Background: Although medicinal carbon (MC) is useful to treat intoxications caused by orally taken toxic chemicals or toxins, high dose of MC is a burden on patients and sticks to oral mucosa or throat. A tablet dosage form of MC is useful to solve such problems. Fast-disintegration, adequate hardness, and quick and high-adsorption potential are required for MC tablets. Method: A modified wet compression method using carboxymethylcellulose sodium (CMC-Na) solution as binder solution was newly developed. Croscarmellose sodium (CC-Na) was used as a disintegration agent. MC granules, binder solution, and MC granules were placed in the cylinder in that order, and the resultant mass was compressed. The obtained tablets were examined for hardness, disintegration rate, and acetaminophen adsorption profiles. Results: The tablets, produced with MC granules containing CMC-Na and CC-Na at 10% each and using 280?μL of 2.5% (w/w) CMC-Na binder solution in compression, showed adequate hardness (more than 4?kg), short disintegration time (less than 6 min), and almost the same acetaminophen adsorption profile as intact MC powder. Conclusion: The modified wet compression with CMC-Na and CC-Na is suggested to be useful to obtain MC tablets with good quality.     

Dissolution and Uniformity Properties of Ordered Mixes of Micronized Griseofulvin and A Directly Compressible Excipient

Abstract

Ordered mixes of micronized griseofulvin were prepared with a commercially available directly compressible excipient. The excipient consisted of a combination of maltose and dextrose and a particle size fraction of approximately 250-850µ was employed in the mixing studies. Ordered mixes containing 0.25%, 0.5%, and 1% active ingredient were prepared and after thirty minutes of mixing, excellent content uniformity of the mixes was seen. Rapid dissolution of drug from the sugar granules was observed when the drug coated granules were tested using the U.S.P. Paddle Method. The ordered mixing process provided an even coat of the micronized drug onto the granules. As the granules dissolved, particle-particle interactions and aggregation problems with the hydrophobic drug were eliminated. The properties of griseofulvin tablets prepared from these ordered mixes were evaluated and the tablets showed excellent content uniformity and rapid dissolution of griseofulvin from the dosage form.     

Effect of glycerol and short sisal fibers on the viscoelastic behavior of wheat flour based thermoplastic

Wheat flour based thermoplastic having glycerol content (20%, 23%, 25%, 30% and 35% w/w) were fabricated using extrusion followed by compression molding. Dynamic mechanical analysis (DMA) has been done with reference to the amount of glycerol, sisal fiber loading, frequency and temperature. Two transitions peaks were observed for the, matrix, one at low temperature, due to the molecular dynamics associated to glycerol rich phase, and another at high temperature attributed to the molecular relaxation of starch rich phase. By changing the amount of glycerol, it has been observed that, at all temperature ranges, a plasticization effect which concerns mainly in the starch rich phase. Introduction of sisal fiber (up to 10% w/w) increases the storage modulus of the thermoplastic matrix. The peak height of damping curves (tan δ) was lowered as the fiber content. The activation energy was calculated from the maximum temperature (T_max) of damping curves.     

Evaluation of Fast Disintegrants in Terfenadine Tablets Containing a Gas-Evolving Disintegrant

Abstract

Effects of four fast disintegrants on the dissolution of terfenadine tablets containing the gas-evolving disintegrant, CaC0₃, were evaluated. In addition, effects of presence of starch along with the fast disintegrants on the dissolution of the tablets were examined. Dissolution data were treated to give dissolution parameters which reflected efficiency of the disintegrant combinations. The four fast disintegrants improved disintegration/dissolution of the original formulation. The relative efficiency of improvement was in the order crospovidone < Ac-Di-Sol < Primojel < low substituted hydroxypropylcellulose. The presence of starch advertently affected the role of the fast disintegrants. Scanning electron microscope studies revealed that starch covered the drug-containing granules and other particles of the tablet. pH changes during dissolution of representative tablets in 0.1 N HCl solutions were determined at specific time intervals. The progressive decrease in rates of acid consumption as a function of the amount of starch, along with the SEM studies, suggested that a barrier existed around the tablet particles. The barrier was generated by the swelled starch grains and was responsible for the loss of the dissolution-improving capacity of the fast disintegrants. Furthermore, the barrier interfered with the diffusion of the hydronium ions and therefore, impaired the function of the disintegrant combination.     

Mechanisms of Drug Release from Matrices Prepared with Aqueous Dispersion of Ethylcellulose

The objective of this study was to investigate the mechanism of acetaminophen (APAP) release from tablets prepared by the wet granulation method using an aqueous polymeric dispersion (Surelease) as a granulating agent. Tablets compressed from granules containing 10% w/w acetaminophen and 13.44% w/w total solids from Surelease released only 52.4% w/w drug after 120 min of dissolution testing, while controlled tablets without Surelease released 94.1% w/w drug. In order to prepare control tablets of 6.8 Kp hardness value, the upper compressional force recorded was 15.87 kN while tablets containing 13.44% w/w of total solids from Surelease had a recorded force of 6.28 kN. The drug release from tablets prepared with Surelease as a granulating liquid followed the diffusion-controlled model for an inert porous matrix     

Effect of Drug,Formulation, and Process Variables on Granulation and Compaction Characteristics of Heterogeneous Matrices: Part II. HPMC and PVP Systems

Abstract

A heterogeneous matrix comprising hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP) at various ratios was granulated using acetaminophen and pseudoephedrine as model drugs. The effect of drug, polymer ratio, total polymer loading, and volume of the granulating fluid on granule growth, granule size distribution, compaction, and tablet properties of the matrix was studied. Formulations containing both acetaminophen and pseudoephedrine required less water to granulate than those containing only acetaminophen. Moreover, the particle sizes of granules prepared with acetaminophen and pseudoephedrine were smaller than those containing only acetaminophen. Tablet hardness increased and friability decreased considerably in all formulations containing pseudoephedrine. In general, the tablet hardness and tablet disintegration time varied with changes in total polymer loading, fraction of HPMC in the matrix, and composition of the model drug(s). All the matrix systems studied showed good flow characteristics at different polymer loadings or HPMC-PVP ratio for matrices formulated with either acetaminophen or both acetaminophen and pseudoephedrine. The results of this study indicate that the presence of drug and/or other excipient(s) in the formulation affects the hydration characteristics of the matrix polymer(s) and compression properties of the granules.     

Increasing the aqueous solubility of acetaminophen in the presence of polyvinylpyrrolidone and investigation of the mechanisms involved

It was shown that the aqueous solubility of acetaminophen in the presence of polyvinylpyrrolidone (PVP) increased. The solubility at 25°C increased from 14.3 mg mL^-1 in the absence of PVP, to 19.7 mg mL^-1 in the presence of 4% w/v PVP, and to 26.7 mg mL^-1 in the presence of 8% w/v PVP. Dialysis studies indicated that there is a potential of binding between PVP and acetaminophen in their aqueous solutions. Dialysis studies also revealed that the nature of interaction between PVP and acetaminophen is physical and reversible, and there was no strong binding between PVP and acetaminophen in their solutions. Infrared spectroscopy of acetaminophen/PVP solid dispersion indicated that the mechanism of interaction between PVP and acetaminophen is via hydrogen bonding. Therefore, the increase in solubility of acetaminophen in the presence of PVP is probably attributed to its ability to form a water-soluble complex with PVP.     

Effects of Hydrophilic Excipients and Compression Pressure on Physical Properties and Release Behavior of Aspirin-Tableted Microcapsules

Aspirin ethylcellulose microcapsules were tableted by compression with or without excipients (lactose or polyvinylpyrrolidone [PVP]). The effects of the amount of the excipients and microcapsule size on the crushing strength and release rate of aspirin from tableted microcapsules were investigated. Tablets without excipients had a crushing strength that was independent of the applied pressure and microcapsule size. An increase in compression pressure from 15 to 60 MPa resulted in an increase in the crushing strength of tablets containing 20% or 40% w/w lactose, but the reverse results were obtained for the tableted microcapsules containing 20% or 40% w/w PVP. Results showed that the release rate of aspirin from microcapsules containing lactose or PVP was independent of the compression pressure with the exception of tablets containing 40% w/w lactose. In vitro release profiles of aspirin from tableted microcapsules containing lactose or PVP showed that increasing the concentration of the excipients resulted in an increase in the release rate of aspirin. Values of n were changed by the compression pressure and the added excipients.     

Continuous direct tablet compression: effects of impeller rotation rate,total feed rate and drug content on the tablet properties and drug release

Context: Continuous processing is becoming popular in the pharmaceutical industry for its cost and quality advantages.

Objective: This study evaluated the mechanical properties, uniformity of dosage units and drug release from the tablets prepared by continuous direct compression process.

Materials and methods: The tablet formulations consisted of acetaminophen (3–30% (w/w)) pre-blended with 0.25% (w/w) colloidal silicon dioxide, microcrystalline cellulose (69–96% (w/w)) and magnesium stearate (1% (w/w)). The continuous tableting line consisted of three loss-in-weight feeders and a convective continuous mixer and a rotary tablet press. The process continued for 8?min and steady state was reached within 5?min. The effects of acetaminophen content, impeller rotation rate (39–254?rpm) and total feed rate (15 and 20?kg/h) on tablet properties were examined.

Results and discussion: All the tablets complied with the friability requirements of European Pharmacopoeia and rapidly released acetaminophen. However, the relative standard deviation of acetaminophen content (10% (w/w)) increased with an increase in impeller rotation rate at a constant total feed rate (20?kg/h). A compression force of 12?kN tended to result in greater tablet hardness and subsequently a slower initial acetaminophen release from tablets when compared with those made with the compression force of about 8?kN.

Conclusions: In conclusion, tablets could be successfully prepared by a continuous direct compression process and process conditions affected to some extent tablet properties.     

Investigations Regarding the Determination of Glass Transition Temperatures from Moisture Sorption Isotherms

Abstract

Moisture sorption isotherm and glass transition temperature (T_g data on polyvinylpyrrolidone (PVP) of molecular weights less than or equal to 40,000 as well as PVP containing added plasticizers were collected to examine the possibility of extracting T, values from moisture sorption data. Moisture sorption isotherms generated for PVP of various molecular weights were similar to those previously reported. The moisture sorption isotherm for PVP-K15 containing added vinylpyrrolidone (VP) and methylpyrrolidone (MP) were predicted reasonably well by simple addition of their respective isotherms with that of PVP-K15. The T_g values for PVP as a function of moisture was similar to that found previously. Decreasing polymer molecular weight or the addition of plasticizers (VP or MP) reduced the T_g of the polymer system, displacing the T_g to lower temperatures. When the moisture content to give a T_g of 25°C (W_g) was indicated on the isotherm, W_g shifted downward with decreasing molecular weight or increasing plasticization by VP or MP while the shape of the isotherm was not distinguishably altered. Consequently, W_g, and thus T_g, would be difficult to extract from the moisture sorption isotherm.     

Tablet Properties and Dissolution Characteristics of Compressed Cellulose Acetate Butyrate Microcapsules Containing Succinyl Sulfathiazole

Abstract

Cellulose acetate butyrate microcapsules of succinyl sulfathiazole were prepared by a modified emulsion-solvent evaporation method and formulated for compression with microcrystalline cellulose and carboxymethyl starch. Tablet hardness decreased and friability increased as microcapsule content increased. Formulations containing up to 50% microcapsules produced satisfactory tablets, but at 70% microcapsules, the tablets were unacceptably fragile. Variation of microcapsule size fraction from 75 μm up to 428 μm had only a small effect on tablet properties when formulated at the 40% level. Tablet hardness increased with increasing compression pressure from 1.9 kg at 17.6 MPa to 14.9 kg at 210.7 MPa. Dissolution properties of the microcapsules were essentially unchanged at compression pressures up to 351 MPa with T_50% values ranging from 121 to 132 minutes. Uncompressed microcapsules had a T_50% value of 130 minutes.     

Carboxymethylstarches in Wet Granulation

Abstract

Commercialized carboxymethystarches (CMS) are both carboxyme-thylated and cross linked potato starch.

The influence of carboxymethylation and cross linkage on the disintegrating properties of starch are studied.

Tablets are made with acetaminophen as drug, Emcompress as diluant, Magnesium stearat as lubricant, and potato starch or its derivatives as disintegrants.

Tablets are prepared by direct compression or by wet granulation with the disintegrant intervening only in internal phasis.

Five disintegrants were studied, with two different concentrations:

native potato starch

potato starch simply cross linked

potato starch simply carboxymethylated

two potato starches both cross linked and carboxymethylated at two different degrees

Compressibility of powders blending and grain for compression are discussed.

The hardness, the tablet disintegration and the rate of drug dissolution are studied.

The results showed that the simply carboxymethylated starch has a totally different behaviour after direct compression or wet granulation. The poor results after wet granulation could be imputed to the bursting of starch granules during grain drying. Since it has lost its granular structure, the carboxymethylated starch will only allow a poor disintegration and a slow dissolution of the drug.

A very similar behaviour of native and simply cross linked starch: the results of which are bad for tablets either prepared by wet granulation or direct compression.

A very similar behaviour of the starches both carboxymethylated and cross linked, allowing a very good disponibility, either with tablets prepared by direct compression or wet granulation. These experiments prove :

the need for an sufficient cross linkage for CMS in a wet granulation process     

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.     

Development of delayed-release proliposomes tablets for oral protein drug delivery

Context: One among many attempts to improve oral protein drug delivery was utilizing the colloidal drug carriers particularly liposomes.

Objective: The purpose was to develop proliposomes of bovine serum albumin (BSA) in the form of granules and delayed-release tablets by using simple tablet manufacturing process.

Materials and methods: BSA proliposomes granules were prepared by spraying 7:3 (w/w) – lecithin:cholesterol solution mixture onto BSA-mannitol granules rotating in a glass coating pan. BSA proliposomes granules were directly compressed into tablets and subsequently coated with Eudragit^® L100 film. The physical properties and stability in gastrointestinal fluids of delayed-release BSA proliposomes tablets as well as reconstituted liposomes were assessed.

Results: The BSA proliposomes tablets disintegrated readily and the obtained reconstituted BSA liposomes exhibited multilamellar vesicles, the size and entrapment efficiency of which were around 2–3 µm and 10–14%, respectively. The delayed-release BSA proliposomes tablets were found to be relatively stable in United States Pharmacopoeia (USP) simulated gastric and intestinal fluids. Increase in amount of BSA in granules resulted in the increase in entrapment efficiency and loading capacity.

Discussion: The Fourier transform infrared spectroscopy (FTIR) results indicated increase in α-helix structure of BSA entrapped in liposomes. ³¹P phosphorous nuclear magnetic resonance spectroscopy (³¹P-NMR) spectrum indicated interaction between BSA molecules and phosphoric acid polar groups of bilayers membrane.

Conclusion: The delayed-release BSA proliposomes tablets developed could completely be reconstituted into liposomes with sufficient resistance to the hostile environment in gastrointestinal tract.     

Comparative pharmacokinetic evaluation of extended release itopride HCl pellets with once daily tablet formulation in healthy human subjects: a two treatment,four period crossover study in fasted and fed condition

Objective: In this study, pharmacokinetics (PKs) and bioavailability of newly developed extended release (ER) Itopride HCl 150?mg encapsulated ER pellets (test) and 150?mg Ganaton ER once-daily (OD) tablets (reference) were compared and evaluated under fasted and fed conditions.

Methods: Twelve healthy human subjects were enrolled in a single dose, randomized; two treatments, two sequences, four period crossover study. A modified and validated liquid chromatographic method was used for the estimation of Itopride HCl in plasma samples. The data were analyzed through non-compartmental model using PK software Phoenix Winnonlin version 7. The outcome was measured on logarithmically transformed data, where p?>?0.05 was considered as non-significant with 90% CI limit of 0.8–1.25.

Results: The C_max, AUC_0–t, and AUC_0–∞ values of Itopride HCl 150?mg ER pellets versus that of OD 150?mg tablets, in fed and fasted states, were within the limits specified by FDA to establish bioequivalence. The relative bioavailability of Itopride HCl 150?mg ER pellets were 1.019 (fed) and 1.081(fasted). The 90% CIs of AUC values for Itopride HCl 150?mg ER pellets and OD 150?mg tablets in fed versus fast were significantly greater and were not within 80–125% limit.

Conclusion: The test and reference formulations had similar pharmacokinetic parameters in each condition studied. However, an increase in the amount of drug was observed in the fed state.     

Application of moisture activated dry granulation (MADG) process to develop high dose immediate release (IR) formulations

Moisture activated dry granulation (MADG) method was used to develop IR tablets with cohesive, fluffy and high dose drugs. To evaluate this approach, three drugs: metformin hydrochloride, acetaminophen and ferrous ascorbate were selected as model compound along with three binders: maltodextrin DE16, PVP K 12 and HPC. The granules were generated using MADG method and tablets were prepared using rotary tablet press. The granules and tablets were characterized for particle size analysis, flow properties, tablet hardness, friability, moisture content, dissolution study, disintegration time and stability study. All results were found to be within acceptable limits. Development of all formulation tablets were found as best fitted for an immediate release of Metformin hydrochloride, acetaminophen and ferrous ascorbate. MADG delivered a robust manufacturing process for generation of granules with excellent flowability. The tablets prepared using this method were found to show better content uniformity, good compactability and low friability. Use of this approach aids to lower the amount of excipients used to overcome physiochemical limitation of the drug substances and there side effects. Both drying and milling steps in wet granulation were not required for MADG process. MADG became a cost effective process which could lead to reduced total tablet size and also save time.