Solubilization of entecavir by povidone to overcome content uniformity challenges for low-dose tablet formulations

Development of 0.1, 0.5, and 1.0?mg entecavir tablet formulations for the treatment of hepatitis B virus was challenging for content uniformity. Entecavir with pK_a of 2.8 and 9.8 does not have sufficient solubility in acidic or alkaline medium or in common pharmaceutical solvents such as ethanol to dissolve the drug in granulating fluid to prepare the homogeneous granulation. Povidone (PVP), a commonly used binder, was found to increase entecavir solubility depending on the PVP concentration and temperature of the solution. At 15% w/w PVP concentration, entecavir solubility increased from 2?mg/mL to about 8?mg/mL at room temperature. When the PVP solution was heated to 50°C or 70°C, the solubility was increased to about 23 or 33?mg/mL, respectively. Based on Raman spectra of entecavir in PVP solution, the increase in entecavir solubility in the presence of PVP may not be due to any molecular interactions between them. Solubilization of entecavir in PVP and eventual granulation did not change the polymorphic form of the drug based on the powder X-ray and differential scanning calorimetric (DSC), and thermo-gravimetric analysis (TGA) of neat entecavir re-crystallized from the PVP solution. The enhancement in the solubility of entecavir by PVP was sufficient to keep the amount of solution, which was used for granulation, to be about 20% w/w of the batch size like the traditional aqueous granulation. The granulation manufactured using this approach provided better tablet content uniformity than one using micronized entecavir.     

Improving the compaction properties of roller compacted calcium carbonate

The effects of roller compaction process parameters, morphological forms of calcium carbonate and particle size of sorbitol on flow, compaction and compression properties were investigated. The morphology of the calcium carbonate and the sorbitol particle size were more influential on the compaction properties than the settings of the roller compactor. The roller compaction process was demonstrated to be robust and stable in regard to flowability and compactibility. The flowability of the granules was improved adequately to facilitate compression in a production scale rotary tablet press. By adding sorbitol to the calcium carbonate, the compressibility - characterized by the Walker coefficient W(ID) - and the compactibility C(P) were improved considerably. A correlation between the consolidation characteristics was demonstrated. Compactibility data from the compaction simulator correlated with the tablet press for two of the calcium carbonates, the cubic form and the ground quality.     

Influence of formulation composition and processing on the content uniformity of low-dose tablets manufactured at kilogram scale

The purpose of this study was to investigate the impact of processing, API loading, and formulation composition on the content uniformity of low-dose tablets made using direct compression (DC) and roller compaction (RC) methods at 1?kg scale. Blends of 1:1 microcrystalline cellulose/lactose or 1:1 microcrystalline cellulose/dicalcium phosphate anhydrous with active pharmaceutical ingredient (API) at loadings of 0.2, 1 and 5% were processed either by DC or RC. A statistical analysis showed that DC produced comparable content uniformity results to RC. Microcrystalline cellulose/lactose formulations had improved average potency compared to microcrystalline cellulose/dicalcium phosphate anhydrous formulations for both DC and RC. The impact of segregation in the DC blends and adhesion to equipment surfaces was assessed to aid in understanding potency trends. DC may be as suitable as RC for low-dose regime (e.g. <?1?mg) when manufacturing clinical supplies at small scale provided the API has a suitable particle size and potency loss to equipment is negligible.     

Systematical approach of formulation and process development using roller compaction

The roller compaction process has gained heightened interest in the pharmaceutical industry. In this review, common excipients and equipment used for dry granulation are described. Roller compaction process parameters and their impact on the critical quality attributes of the final product, as well as evaluation methods for roller compaction product such as ribbons and granules, are discussed. Overall, a systematical approach of formulation and process development has been proposed for excipient selection, critical process parameter identification, and necessary tests.     

Reducing dust and improving granule and tablet quality in the roller compaction process

The dramatic reduction of non-compacted material during roller compaction and an important improvement of the granule and tablet qualities were obtained by a controlled wetting process before the roller compaction. The continuity of the roller compaction process was maintained by using a continuous fluid bed system. Due to a controlled water addition, a better binder distribution was obtained than when using micronised dry binders. When dry compacting poorly water soluble hydrochlorothiazide mixtures, the resultant dissolution rate was not influenced by the HPMC binder viscosity. When moistened blends were compacted, the resultant dissolution rate decreased with increasing HPMC binder viscosity. The roller compaction pressure had almost no influence on the drug dissolution rate. The addition of disintegrants did not improve the dissolution rate. When a fraction of the filler α-lactose monohydrate was replaced by microcrystalline cellulose, the dissolution rate increased with an increasing microcrystalline cellulose fraction. With the addition of 0.5% Tween® 80 to a formulation containing 25% microcrystalline cellulose and 50% α-lactose monohydrate, the dissolution rate increased and an immediate release tablet formulation was obtained. The presence of microcrystalline cellulose also improved the processing and avoided lump formation.     

Mechanistic study of the effect of roller compaction and lubricant on tablet mechanical strength

Heckel analysis, tablet tensile strength, and indentation hardness were determined for a series of sieved and roller compacted microcrystalline cellulose mixtures under both unlubricated and lubricated conditions with magnesium stearate. These results have been used to evaluate the loss of reworkability following roller compaction for microcrystalline cellulose and show the extent of impact on tableting properties when magnesium stearate is added intragranularly prior to roller compaction. While results consistent with traditional work-hardening are observed as shown by a modest increase in dynamic hardness and mean yield pressure for unlubricated, roller compacted microcrystalline cellulose, it is overshadowed by the overlubrication effect seen during roller compaction and in particular, the subsequent milling step. The common practice of lubricating the feedstock with magnesium stearate to avoid sticking of the material to the compaction rolls appears to be the major cause of decreased mechanical strength of the final compressed tablets.     

Simulation of roller compaction using a laboratory scale compaction simulator

A method for simulation of the roller compaction process using a laboratory scale compaction simulator was developed. The simulation was evaluated using microcrystalline cellulose as model material and ribbon solid fraction and tensile strength as key ribbon properties. When compacted to the same solid fractions, real and simulated ribbons exhibited similar compression behavior and equivalent mechanical properties (tensile strengths). Thus, simulated and real ribbons are expected to result in equivalent granulations. Although the simulation cannot account for some roller compaction aspects (non-homogeneous ribbon density and material bypass) it enables prediction of the effects that critical parameters such as roll speed, pressure and radius have on the properties of ribbons using a fraction of material required by conventional roller compaction equipment. Furthermore, constant ribbon solid fraction and/or tensile strength may be utilized as scale up and transfer factors for the roller compaction process. The improved material efficiency and product transfer methods could enable formulation of tablet dosage forms earlier in drug product development.     

Development and optimization of a novel sustained-release dextran tablet formulation for propranolol hydrochloride

A novel oral controlled delivery system for propranolol hydrochloride (PPL) was developed and optimized. The in vitro dissolution profiles of sustained-release matrix tablets of racemic PPL were determined and compared with the United States Pharmacopeia (USP) tolerance specifications for Propranolol Hydrochloride Extended-Release Capsules. The influence of matrix forming agents (native dextran, hydroxypropyl methylcellulose (HPMC), cetyl alcohol) and binary mixtures of them on PPL release in vitro was investigated. A central composite design was applied to the optimization of a sustained-release tablet formulation. The sustained-release matrix tablets with good physical, mechanical and technological properties were obtained with a matrix excipient:PPL ratio of 60:40 (w/w), with a dextran:HPMC ratio of 4:1 (w/w) and with a cetyl alcohol amount of 15% (w/w). A comparative kinetic study of the present matrix tablets and commercial SUMIAL RETARD capsules (Spain) was established. The value for the similarity factor (f(2)=69.6) suggested that the dissolution profile of the present two sustained-release oral dosage forms are similar. Higuchi (diffusion) and Hixon-Crowell (erosion) kinetic profiles were achieved and this codependent mechanism of drug release was established.     

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.     

Prediction of drug particle size and content uniformity in low-dose solid dosage forms

Drug particle size distribution has a profound impact to the content uniformity in low-dose solid drug products. We derived theoretically the skewness of potency distribution as a function of particle size distribution and target dose. It was demonstrated that both skewness and coefficient of variation diverge simultaneously with inverse square root of the target dose. This scaling relation was observed in recent experiment and was verified by Monte Carlo (MC) simulation, which was employed for the first time to solve for the full potency distribution from a random retrieving model. When tested against the criteria from USP 〈905〉 uniformity of dosage units, MC simulation showed a striking anisotropic distribution of the data. This suggests a full-scale consideration of the potency distribution is necessary for evaluating the impacts from particle size distribution and the dose, as compared against the normality assumption used before. A nomograph of the median particle size and the dose that meets a 99% pass rate was constructed for the specification of particle size or the lowest dose limit. Furthermore, we showed quantitatively the lowest dose limit can be drastically reduced if a cut-off size is imposed by removing oversized particles.     

Monitoring the acoustic activity of a pharmaceutical powder during roller compaction

Acoustic relaxation emissions (ARE) from microcrystalline cellulose (MC) and maize starch (MS) were detected during roller compaction using a microphone with flat frequency response up to 20 kHz and a tunable high pass filter the limiting frequency of which was set at 15 kHz. The noise from the compactor itself was found to appear mainly below 15 kHz. The ARE intensity of MC was observed to increase as a function of applied compressive force up to 45 kN, while the ARE intensity–force curve of MS had a maximum at 50 kN. A Gaussian-shaped function fitted reasonably to the data in both cases.     

Influence of physical factors on tablet splitting, weight and content uniformity of atenolol tablets

Tablet splitting is widely practiced worldwide. Several studies have considered weight variation of split tablets as a mean of estimating drug content uniformity but the analysis of their drug content and physical factors that may affect splitting are limited. The aim of this study is to evaluate the impact of manufacturing parameters and splitting on content and weight uniformity of atenolol tablets. Atenolol tablets (100 and 50?mg) were prepared under the same manufacturing conditions and using the same excipients. The obtained tablets were checked for hardness, weight, and disintegration. The weight and the content of the two strength atenolol tablets after splitting into two halves were evaluated. Atenolol tablets (100?mg) showed higher values of hardness, disintegration time and diameter than atenolol tablets (50?mg). Atenolol tablets (100?mg) passed both weight and content uniformity while atenolol tablets (50?mg) failed these tests. Half tablet weight appears to be directly correlated with its drug content. Manufacturers should investigate physical factors such as tablet hardness, diameter, and disintegration time that may play an important role in achieving both weight and content uniformity in the resultant tablet halves.     

新型恩替卡韦制剂的药代动力学研究

目的测定大鼠血浆中恩替卡韦含量的液相色谱-串联质谱(LC-MS/MS)生物分析方法学的建立和验证以及新型恩替卡韦新制剂的药物代谢动力学研究。方法建立了测定大鼠血浆中恩替卡韦含量的液相色谱-串联质谱生物分析方法,并对所建立生物分析方法进行了方法学验证;然后,采用验证过生物分析方法在健康雄性Wistar大鼠体内对新型恩替卡韦制剂和原研药博路定片进行了非禁食情况下药物代谢动力学对比研究。结果方法学验证实验结果表明所建立的生物分析方法学符合相关验证要求;新型恩替卡韦制剂和原研药博路定片的血浓时间线下面积(AUC)分别为(672.5±65.7)和(461.3±10.9)ng·h·m L~(-1),并且这两种制剂所对应的半衰期(t1/2)分别为(11.06±3.21)和(6.66±0.92)h。结论试验结果表明在非禁食情况下新型恩替卡韦片剂明显优于原研药博路定片,新型恩替卡韦制剂的生物利用度(AUC)比博路定片提高了46.1%,并且将半衰期(t1/2)延长了67.1%。这些数据表明与原研药博路定片不同的是食物没有降低新型恩替卡韦片的生物利用度,因此,新研发的新型恩替卡韦制剂提高了疗效,有效地克服了原研药博路定片的食物影响。     

Multiple compaction of microcrystalline cellulose in a roller compactor.

The effect of multiple roller compaction was investigated using microcrystalline cellulose as a model substance. Granules were prepared, examined and recompacted in a Gerteis 3 W-Polygran roller compactor up to ten times. Examinations were carried out for granule size distribution, density and flow properties. Ribbons were investigated for quality, and adhesion of ribbons to the rolls was traced. Finally tablets were produced from the granule samples and examined for their compression behaviour. Multicompression reduces the amount of fines, increases mean granule size and flow properties and also improves size distribution. Although roll adhesion diminishes with increasing cycles, this decrease is not sufficient enough to result in a visibly reduced gap variability. By multicompaction, bulk density increases which indicates that the porosity of granules decreased during the multiple compaction cycles. However, the ability of MCC to form bondings with neighbouring particles is diminished during various cycles which results in decreasing crushing forces of the subsequently prepared tablets.     

Application of process analytical technology in tablet process development using NIR spectroscopy: blend uniformity, content uniformity and coating thickness measurements

Near-infrared (NIR) spectroscopy was employed as a process analytical technique in three steps of tabletting process: to monitor the blend homogeneity, evaluate the content uniformity of tablets and determine the tablets coating thickness.

A diode-array spectrometer mounted on a lab blender (SP15 NIR lab blender) was used to monitor blend uniformity using a calibration-free model with drug concentration ranging from 2.98 to 9.25% (w/w). The method developed accurately depicted the changes in concentration of the drug during blending and the positive effect of a delumping step in the production process. Blend homogeneity was reached within 2 min of the blending step post-delumping, with relative standard deviation (R.S.D.) values varying from 1.0 to 2.5% depending on the drug concentration of the blend.

A Fourier-transform spectrometer (Bruker MPA) was used to analyze content uniformity and coating thickness with calibration based models. Prediction of a validation set with tablets compacted at pressures not present in the calibration set yielded an root mean square error of cross validation (RMSEP) of 1.94%; prediction of tablets compacted at pressures present in the calibration set yielded a RMSEP of 1.48%. Performance of the model was influenced by several physical tablet properties, which could be reduced by spectral pre-processing.

A model based on reflectance spectra predicted coating thickness and its variation more accurately than the model based on transmission spectra. Inter-tablet coating variation was predicted with NIR and compared to reference thickness measurements. Both methods gave comparable results. Initial inter-tablet variation of tablets sampled in-process during coating was high, but stabilized after 30 min into the process.     

A method for content uniformity determination of atenolol and losartan potassium in combined tablet dosage form

A simple, accurate, rapid, specific and reproducible UV spectrophotometric method was developed for estimation of content uniformity of atenolol and losartan potassium in its combined tablet dosage form. The method involves formation and solving the simultaneous equation using 226.4 and 254 nm as two wavelengths for atenolol and losartan, respectively. Developed method was employed to determine the atenolol and losartan content in ten individual tablet units of five market formulations. Methanol was used as solvent. The method was validated. From the results, it was concluded that all brands are within the content uniformity limit, 85-115%.     

Effect of spatial distribution of contaminant microorganisms within tablet formulations on subsequent inactivation through compaction

A wet granulation process, employing an aqueous suspension of Bacillus megaterium spores as binder, was used to prepare contaminated granules of three direct compression vehicles, Emdex, lactose and potassium chloride. Granules were also prepared with sterile water as binder and directly contaminated by dry mixing with B. megaterium spores, as were the original direct compression vehicles. Particle size distributions for the granules and the direct compression vehicles were similar. Survival of B. megaterium was assessed, following compaction (500 mg) at various pressures (0–271 MN · m⁻²) using a 1 cm flat-faced punch and a 10 ton hydraulic press. In all cases the degree of killing was directly proportionate to the compaction pressure. For those materials compacting by fracture, lactose and Emdex, then the degree of killing was similar for the dry contaminated direct compression vehicle and those granules prepared with contaminated binding fluid, but significantly greater in the dry contaminated granules and greater overall for lactose rather than Emdex. For potassium chloride, a material which plastically deforms, then the degree of killing was significantly enhanced by incorporation of the contaminant into the binding fluid.     

Gastrointestinal transit of a controlled release naproxen tablet formulation

The gastrointestinal transit of a controlled release naproxen tablet formulation has been measured in healthy young and old subjects using the technique of gamma scintigraphy. Gastric emptying of the tablet was affected by food (mean emptying times for fasted subjects were 0.64 h (young) and 0.86 h (old) increased to 3.0 h (young) and 3.3 h (old) following a light breakfast). The small intestinal transit times for both fed and fasted states was about 3.2 h. There were no significant differences that could be attributed to subject age for gastric emptying and small intestinal transit.     

The roller compaction of different types of lactose

The influence of the roller compaction process on the granule quality of four different types of lactose showing different particle size, bulk density, crystallinity and morphology was compared by modeling. For each type of lactose the influence of the parameter settings on the friability was modeled by a second order polynomial having different average relative deviation values. Pressure, roll speed, vertical and horizontal screw speed were important parameters for all types of lactose but pressure was the most important parameter followed by the roll speed and the horizontal screw speed. Type, particle size and density had an influence on the usable roller compactor parameter settings. The best quality was obtained if at a high pressure a low horizontal screw speed was chosen for each roll speed. Roller compaction of spray-dried lactose was difficult. A gradual decrease of granule quality was seen for α-lactose monohydrate 200M, anhydrous β-lactose, α-lactose monohydrate 90M and spray-dried α-lactose, respectively. The roller compaction process using the different types of lactose was reproducible.