Effect of drug content and drug particle size on the change in particle size during tablet compression.

Three size fractions for each of three poorly soluble drugs were compressed into 10 mm diameter tablets of four different dilution ratios. The compression was carried out on a physical testing instrument at four compression levels of 49.0, 98.1, 196.2 and 294.3 MN m-2. The effect of drug content and drug particle size on the change in particle size during tableting was examined by the determination of the dissolution rate for disintegrated tablets. A linear relation was obtained when plotting 1n(T80%) versus drug content. There was a critical particle size where the phenomena of cleavage and bonding during tableting balanced each other, but this varied with drug content.     

Evaluation of changes in drug particle size during tableting by measurement of dissolution of disintegrated tablets

Three poorly soluble drugs (chloramphenicol, phenacetin and prednisolone) were compressed into tablets of 10% drug content on a physical testing instrument at three different compression pressures. The dissolution profiles were determined by a modification of the U.S.P. method for drug suspensions, granules before compression, disintegrated and intact tablets. By comparison of the dissolution rates for disintegrated tablets with those for granules before compression, or suspensions, it is possible to separate the change in particle size during compression from the pressure-dependent dissolution behaviour of intact tablets. A comparative measurement of dissolution for disintegrated tablets with that for granules provides a useful method for elucidating the particle bonding or cleavage within the tablet during compression.     

Evaluation of changes in drug particle size during tableting by measurement of dissolution of disintegrated tablets.

Three poorly soluble drugs (chloramphenicol, phenacetin and prednisolone) were compressed into tablets of 10% drug content on a physical testing instrument at three different compression pressures. The dissolution profiles were determined by a modification of the U.S.P. method for drug suspensions, granules before compression, disintegrated and intact tablets. By comparison of the dissolution rates for disintegrated tablets with those for granules before compression, or suspensions, it is possible to separate the change in particle size during compression from the pressure-dependent dissolution behaviour of intact tablets. A comparative measurement of dissolution for disintegrated tablets with that for granules provides a useful method for elucidating the particle bonding or cleavage within the tablet during compression.     

The effects of polymorphism,particle size and compression pressure on the dissolution rate of phenylbutazone tablets

The dissolution rate of phenylbutazone from tablets after disintegration has been used to determine whether the drug particles underwent crushing or bonding during compression. Two polymorphic forms of the drug were used and the predominant effect for high drug concentration (60%), during compression was dependent upon the original particle size of the drug and its polymorphic form. With a low drug concentration (10%) in the tablet, the diluent protected the drug particles from bonding together. The particle size change of the drug during compression was affected by the nature of the diluent present. Lactose had an abrasive action on Form A phenylbutazone compared with Avicel but had little effect on the more ductile Form B. When the contact time of compression was decreased from 29 to 0·-26 s, the 6 μm particles of drug showed less bonding at the shorter time (faster rate of compression) but the effect observed with the larger particles was independent of the compression rate.     

Granule size distribution of tablets

The purpose of this study was to determine the variation in the granule size distribution in a die of an eccentric tableting machine. Theophylline anhydrate and α‐lactose monohydrate were granulated with an aqueous solution of polyvinylpyrrolidone, using an instrumented fluid bed granulator. The granules were tabletted, using an instrumented eccentric tableting machine. Punch forces were recorded and tablets were collected in order during the tableting process. Powder samples, which had the same mass as the tablets, were also collected from the die for particle size determination. The particle size distribution was measured, using a spatial filtering technique. In addition, the segregation of microcrystalline cellulose pellets during tableting was analyzed. The particle size distribution changed dramatically during the tableting process, due to a segregation phenomenon. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2061–2069, 2010     

Determination of deferasirox particle size distribution via laser diffraction and its application in establishing a correlation between particle size and drug dissolution in vitro

Deferasirox is the first-line drug for iron overload due to thalassemia in adults and pediatric patients. It is classified as a type II compound in the Biopharmaceutics Classification System, and thus the particle size of its active pharmaceutical ingredient (API) should be strictly controlled during the manufacturing process. In the present study, laser diffraction was adopted to measure the particle size distribution of deferasirox API. We also developed and validated an accurate and convenient method by investigating important optical parameters and sample dispersing conditions. The relative standard deviation values, namely, d (0.1), d (0.5), d (0.9), and d (4,3), measured via methodology validation and actual sample measurement were < 3%. The dissolution curves of several batches of dispersible tablets prepared using deferasirox with different particle sizes were compared in the four dissolved media to investigate the influence of particle size on drug dissolution in vitro. Results indicated that the particle size distribution of deferasirox API significantly affected the release of its dispersible tablet.     

Quantification of Fragmentation of Pharmaceutical Materials After Tableting

Deformation is the material property that is a key for successful tablet formulation. Still, a quantitative method for assessing the change in particle size as a result of compression is lacking. The purpose of this study is to introduce a method for quantifying fragmentation after tableting. Different size fractions of dibasic calcium phosphate, microcrystalline cellulose, lactose, and starch were blended with magnesium stearate and compressed into tablets. The compressed particles were recovered from the tablets by manual grinding, which was possible by the addition of magnesium stearate. The recovered particles were subjected to scanning electron microscopy and particle size distribution (PSD) analysis. Fragmentation was quantified by characterizing the change in PSD. PSDs of the compressed samples with increasing compression pressures were analyzed, and more specifically, the particle sizes from the inflection point were used to generate a fragmentation profile. The fragmentation profiles of dibasic calcium phosphate and lactose showed extensive fragmentation during tableting; microcrystalline cellulose fragmented slightly, whereas starch did not fragment at all. The results furthermore showed that the mechanical strength of the tablet was highly dependent on fragmentation, as the mechanical strength did not start to increase before almost all fragmentation had occurred. Hence, by using this method, it is possible to quantify at which compression pressure and to which degree materials fragment during the tableting process.     

Determination of segregation tendency of granules using surface imaging

In this study, powder surface imaging was utilized in evaluation of particle size-related segregation behavior of granules during vibration and tableting processes. Altogether, eight granule batches were manufactured using a fluidized bed granulator. The particle size distribution of each batch was measured with sieve and image analysis. Segregation tendency of the batches was studied by a vibrational measurement setup. In addition, segregation during tableting was studied by taking samples during the tableting process. Image analysis was utilized to analyze the segregation in both cases. Roughness parameters (Ra) were calculated from images taken during simulation of segregation. In addition, weight variation of tablets was calculated. Finally, principal component analysis was used to visualize the effect of specific particle size fractions on segregation tendency of granules. According to the results, a broad particle size distribution and large particle size can inflict problems during tableting. Surface imaging was an efficient method to monitor the segregation tendency of granules during vibration and tableting. In addition, the segregation tendency of a granular material can be directly linked to weight variation of tablets during tableting and thus be used in a predictive manner.     

Dissolution from tablets prepared using ethyl cellulose microcapsules

Microcapsules containing sodium phenobarbitone cores in ethyl cellulose have been used to prepare tablets at from 3·9 to 358·9 MPa compression pressures. The tensile strength of these tablets is related linearly to the core: wall ratio and to the microcapsule size. Dissolution of the drug from the microcapsules is also related to the core: wall ratio and microcapsule size, but except at low compression pressures is almost independent of the pressure used during preparation. The tablet matrix remains intact during the dissolution and the equations developed by Schwartz, Simonelli & Higuchi (1968) are followed. Large microcapsules of 1:2 core:wall ratio produce friable tablets with rapid release of contents.     

Influence of particle size and shape on flowability and compactibility of binary mixtures of paracetamol and microcrystalline cellulose.

The influence of the size and shape of paracetamol particles on the flow and compression behavior of blends (1:1) of microcrystalline cellulose (MCC) was investigated. The effect of paracetamol particle shape was investigated by using two differently prepared samples, micronized and novel engineered Solution Atomization and Xstallization by Sonication (SAXS) particles, which exhibited similar particle size ranges (2-6 microm). The results were compared to data obtained for an untreated paracetamol sample. The blends containing SAXS particles exhibited increased bulk and tapped density and improved flow, compared to the blend containing micronized particles. This may reflect differences in shape since the SAXS particles exhibited spherical morphology. The compressibility of the blend containing untreated paracetamol was greater than blends containing the SAXS and micronized materials, which may reflect the different drug particle sizes and shapes. However, blends containing the needle-shaped particles of pure untreated sample, exhibited poor compactibility after storage at 10% RH. It was found that increasing the moisture content in the blends by storage at 44% RH resulted in an increase in the compactibility of the samples containing untreated and SAXS paracetamol with the blends containing micronized paracetamol being relatively unaffected. In general, tablets prepared from blends containing smaller particles of paracetamol exhibited significantly greater compactibility compared to tablets prepared containing the larger particle sized untreated paracetamol. The use of small, spherical drug particles may result in improvements in the bulk density, densification and compactibility of blends of paracetamol and microcrystalline cellulose.     

Metered-dose inhalers I: drug content and particle size distribution of beclomethasone dipropionate

Four commercially available beclomethasone metered dose inhalers were analyzed for both spray content uniformity and particle size. The drug contents of primed and unprimed sprays collected at the beginning of the lifetime of the canister were not significantly different from those collected throughout the experiment. Particle size analysis of the four products using the Anderson Cascade Impactor Mark II showed that the distribution profiles were not identical.An existing HPLC method was modified to quantitate single sprays for content uniformity and to measure the amount on an impactor stage for particle sizing.     

Investigating the effect of particle size and shape on high speed tableting through radial die-wall pressure monitoring

Investigating particle properties such as shape and size is important in understanding the deformation behavior of powder under compression during tableting. Particle shape and size control the pattern of powder rearrangement and interaction in the die and so the final properties of the compact. The aim of this study was to examine the effect of particle size and shape on compactability. Particle friction and adhesion were investigated through radial die-wall (RDW) pressure monitoring. To fulfill this aim, powders and granules of different sizes and shapes of materials with different compaction behaviors were used. Compaction simulation using the Presster with an instrumented die was applied. Small particle size increased residual die-wall pressure (RDP) and maximum die-wall pressure (MDP) (p<0.05) for plastic and viscoelastic materials, respectively, while big particle size had an opposite effect. No effect was found on brittle material, however big particle size showed higher friction for such materials. Regarding morphology, fibrous elongated particles of microcrystalline cellulose had less friction tendency to the die-wall in comparison to rugged surface mannitol particles. RDW pressure monitoring is a useful tool to understand the compactability of particles in respect to size and shape.     

Effect of drug particle size on content uniformity of low-dose solid dosage forms

Two low-dose blends were prepared that differed only in the particle size of the drug used to make the blends. The geometric mean particle diameters for the two lots of drug used were 18.5 and 6.1μm. Samples of the blends approximately equivalent to the unit dose of 10 μg per 99 mg of blend were assayed for potency. For the blend containing the larger particle size drug, the potency range was 88–130% (n = 65) compared to 97–102% (n = 64) for the blend containing the smaller particle size drug. A simple computer method was able to qualitatively simulate the observed potency profiles using only the particle size distribution of the drug and assuming ideal mixing. The method provides guidance in setting particle size specifications to avoid poor content uniformity.     

The influence of drug and diluent particle size on the in vitro release of drug from hard gelatin capsules

The in vitro release of a drug from capsules containing different proportions of controlled particle size fractions of acetylsalicylic acid and lactose, has been assessed in terms of the time for 50% of the drug content of the capsule to be released into solution during a dissolution test (T50), and by a standard disintegration test. In general the two types of test gave closely related responses although some discrepancies existed with certain systems. For capsules containing only the drug, the value of T50 increased as the particle size of the drug decreased. The addition of lactose generally reduced the T50 value, the extent of the reduction showing greater dependence on the proportion of lactose added than its particle size. Capsule formulations containing 80% w/w of lactose had values of T50 which were independent of drug or diluent particle size. Capsule formulations containing lower proportions of lactose usually had an optimum combination of particle size fractions of drug and diluent for maximum drug release. The relationship between drug release and the porosity within the capsule was dependent on the particle size of the drug.     

处方工艺对瑞舒伐他汀钙片混合均匀度及含量均匀度的影响

目的 研究处方中的辅料及工艺对瑞舒伐他汀钙片混合均匀度及含量均匀度的影响。方法 采用粉末直接压片工艺，通过单因素试验，考察处方中乳糖的型号、微晶纤维素的型号、乳糖与微晶纤维素的比例、钙盐的种类及交联聚维酮用量对混合均匀度及含量均匀度的影响；同时研究混合工艺对混合均匀度及压片工艺对含量均匀度的影响。结果 不同的乳糖型号（T80、PW80、315）、微晶纤维素型号（PH102、M102、102）、乳糖与微晶纤维素的比例（1:1、3:1、1:3）、钙盐的种类（磷酸钙（细颗粒）、无水磷酸氢钙（细颗粒、细粉）、碳酸钙（细粉））的处方混合均匀度及含量均匀度良好，磷酸钙（粗颗粒）的处方混合均匀度及含量均匀度较差。在混合容器中加入50%的乳糖，之后加入原料药、微晶纤维素、交联聚维酮和磷酸钙，以10 r·min-1混合20~25 min；再加入剩余的乳糖，以10 r·min-1混合15~25 min，物料混合均匀度良好。重力加料器及压片速度（10~20 r·min-1）的含量均匀度良好；强制加料器及压片速度（30 r·min-1）的含量均匀度较差。结论：通过研究筛选出了适合粉末直压工艺的乳糖型号、微晶纤维素型号、乳糖与微晶纤维素比例、钙盐种类及交联聚维酮用量。考察了混合工艺参数范围，优选了重力加料器及压片速度（10~20 r·min-1），获得了良好的混合均匀度和含量均匀度。     

The influence of drug and diluent particle size on the in vitro release of drug from hard gelatin capsules

The in vitro release of a drug from capsules containing different proportions of controlled particle size fractions of acetylsalicylic acid and lactose, has been assessed in terms of the time for 50% of the drug content of the capsule to be released into solution during a dissolution test (T50), and by a standard disintegration test. In general the two types of test gave closely related responses although some discrepancies existed with certain systems. For capsules containing only the drug, the value of T50 increased as the particle size of the drug decreased. The addition of lactose generally reduced the T50 value, the extent of the reduction showing greater dependence on the proportion of lactose added than its particle size. Capsule formulations containing 80% w/w of lactose had values of T50 which were independent of drug or diluent particle size. Capsule formulations containing lower proportions of lactose usually had an optimumcombination of particlesize fractions of drug and diluent for maximum drug release. The relationship between drug release and the porosity within the capsule was dependent on the particle size of the drug.     

Changes in the particle size distribution during tableting of sulphathiazole powder.

Five size fractions of sulphathiazole powder (volume surface mean diameter 155, 133, 86, 50 and 41 mum) were compressed into 12 mm diameter tablets on an instrumented single punch tablet machine. The size analysis of the tablet material after compression showed an attrition of the coarser fraction and an agglomeration of the finer fraction. It is postulated that there is a critical particle size where the effects of crushing and bonding cancel each other. The changes in particle size are discussed in relation to some of the compressive characteristics of the powder.     

Effects of tableting pressure on hydration kinetics of theophylline anhydrate tablets.

The effects of tableting pressure on hydration kinetics of types I and II theophylline anhydrate tablets at 95% relative humidity, 35 degrees C, have been studied by using various kinetic equations. Relations between tablet expansion and hydration were studied. Samples of 2 cm diameter tablets (1 g) were compressed at 5, 10 and 20 MPa. The hydration of types I and II tablets decreased with increased tableting pressure. The time required for 50% hydration of 2 cm diameter tablets, compressed at various pressures suggests that the tablet hydration rate was affected by the tableting pressure. Types I and II tablets expanded 11.37-16.75% in volume during hydration to the monohydrate. The thickness expansion of the tablets exceeded the diameter expansion as the tablet structure was not uniform owing to the orientation of particles during the compression. The final expansion ratio of the tablets increased with increased tableting compression pressure. The Hancock Sharp constant (m) and fitting of the kinetic data to a suitable model suggested that the hydration of theophylline anhydrate tablets followed the two-dimensional phase boundary equation (type I tablets) or the three-dimensional phase boundary equation (type II tablets).     

提高难溶性药物尼群地平溶出率和口服生物利用度的研究

目的通过制剂手段提高难溶性药物尼群地平的体外溶出率和家犬体内的相对生物利用度。方法用共研磨法制备研磨混合物,并用差热分析法、X射线衍射法、显微镜法鉴别药物在共研磨混合物中的存在状态,在此基础上采用直接压片法制备口腔速崩片,测定体外溶出速率,所有试验均以物理混合物为参照进行比较;用HPLC法测定3只健康家犬分别口服尼群地平口腔速崩片(受试制剂)、市售普通片(参比制剂)后不同时间血浆中尼群地平的浓度,计算药物代谢动力学参数及相对生物利用度。结果共研磨混合物中尼群地平的粒径远小于物理混合物,并以微晶状态存在;以共研磨混合物制备的口腔速崩片的溶出速度和程度均大于以物理混合物制备的口腔速崩片;在家犬体内受试制剂和参比制剂的tmax分别为1.5 h和4.25 h,ρmax分别为176.54μg.L-1和111.12μg.L-1,AUC0-t分别为903.78μg.h.L-1和651.99μg.h.L-1,AUC0-∞分别为1 030.46μg.h.L-1和903.68μg.h.L-1,受试制剂的相对生物利用度为138.5%;受试制剂的体内吸收和体外溶出速率均高于参比制剂。结论通过制备共研磨混合物和口腔速崩片的方法,提高了尼群地平的体外溶出度和家犬体内的相对生物利用度。     

The vibratory consolidation of particle size fractions of powders

The use of controlled sinusoidal vibration as a means of consolidating packings of lactose within small containers has been examined. Vertical vibration was found significantly more effective and reproducible than horizontal vibration in terms of the degree of consolidation achieved. An optimum frequency range was identified within which the densification was greatest, and this range was largely independent of particle size for particle size fractions of mean volume diameters ranging from 15.6 to 155 μm. The consolidation increased with increasing vibration acceleration up to a level beyond which no further decrease in porosity resulted. Typical effective vibration conditions were characterized by amplitudes of an order of magnitude similar to the particle sizes studied. For particle size fractions of mean diameters 17·8, 37·5 and 80·8 μm, there is evidence that an optimum particle size range exists, within which energy requirements for consolidation are at a minimum.