Quality assurance in pharmaceutical powder processing: Current developments

Abstract

Pharmacopoeia1 requirements relating to standardization of the physical performance of oral dosage forms containing powders are usually limited to tests on the final product.

Such tests are aimed at ensuring that all tablets or capsules have the correct, nominal, drug content and that the drug is released into solution within a specified time. Whilst dissolution or disintegration test to assess drug release can only be carried out on a finished dosage form, content uniformity tests currently carried out on tablets or capsules alone could also be usefully carried out earlier on component powders at different stages during processing. The aim of developing a quality assurance procedure for quantifying the homogeneity of powders prior to tablet compaction or encapsulation would be to pin-point more precisely the part of a process where content uniformity problems arise. Secondly, a good quality assurance procedure would provide full mechanistic information about the behaviour of a given powder system, so that appropriate remedies could be applied.

Eleven different methods of testing homogeneity of powder mixes have been cited in pharmaceutically oriented literature and these will be reviewed in terms of their usefulness as routine quality assurance procedures for drug content uniformity. Of these 11 methods, 2 test methods were considered to be especially useful: one based on a flow test and the other on vibration analysis. This techniques has been validated using a complete vibration analysis and testing rig under conditions encountered during routine powder processing.

It would be desirable to see standard powder mixes tested on apparatus of the same design in different laboratories as a means of assessing the reproducibility of the proposed quality assurance method when used by different personnel.     

Validation of the Content Uniformity Testing of USP XXI (1985) for Tablets Containing Potent Drugs

Abstract

The content uniformity of tablets containing high potency, low dosage drugs can only be successfully maintained by application of GMP at all stages of the total manufacturing process including both formulation and quality control. This requires both understanding of the pharmaceutical technology involved and appropriate designing of content uniformity test.

The USP XXI (1985) has made the content uniformity test more stringent by applying both tests by attributes and variables, In this study the test has been challenged by using 27 batches of ethinyloestradiol 10 μg tablets having different degrees of homogeneity in powder mixes and tablets.

The results indicate that the test has a weak potential in determining the content uniformity of batches prepared from cohesive drug powders and characterised by skewed distribution of drug content in tablets. It is the same drawback of the USP XX (1980) content uniformity test. This defect is due to the small sample size of 10 unit doses in the first step which is not sufficient to detect the presence of unit dosages containing high drug content in a batch of tablets hawing skewed distribution. Statistical analysis of the results using coefficient of skBwness and nonparametric Lilliefors test has shown that some batches which have passed the USP XXI (1985) content uniformity test are pharmaceutically unacceptable. This indicates the importance of incorporating within the official specifications a test which includes an examination of the type of distribution and hence, increasing sample size is required.     

Evaluation of Spray-Drying as a Method to Prepare Microparticles for Controlled Drug Release

The possibility to obtain microcapsules or microspheres for controlled release by spray-drying is evaluated. Drugs of different solubilities like theophylline and sodium sulfamethazine, with Eudragit RS as coating polymer, are chosen.

The polymer is used, either dissolved in an hydroalcoholic solution or suspended (pseudolatex) in water, in different weight ratios with the drug. The obtained solution or suspension is spray-dried.

Scanning electron microscope analysis of the powders reveals no sign of microencapsulation. Moreover, only a fraction of the particles has a spherical shape.

For each spray-dried powder, a part of the obtained particles is compressed into tablets, and the rest is stored.

Dissolution studies in distilled water at 37 C are performed on powders and tablets.

While the uncompressed microparticles do not give any controlled release, the tablets show an ability in slowing down drug delivery greater than the one obtained with the traditional methods.     

Studies of Hie Effect of Powder Moisture Content on Drug Release from Hard Gelatin Capsules

The in vitro dissolution of model formulations from hard gelatin capsules containing drug: diluent powder mixtures at different moisture levels has been studied. The capsules were filled to a constant porosity of 50%. to contain either sodium barbitone or barbitone in 50:50 mixture with lactose or maize starch, the latter at one of three moisture levels. In addition, capsules containing drug alone were examined. The wettability and polarity indeces of the individual powders and binary mixtures, as well as the permeability and liquid penetration rates of powder beds were also determined.

The presence of either excipient was found to modify the time for 50% drug dissolution (t₅₀) compared with drug alone for all formulations examined, apart from the sodium barbitone: lactose capsules. The rate of drug dissolution was also dependent on the initial powder moisture content for the drug:starch formulations. Open storage of capsules at 20^%/75%. R.lt. generally increased t₅₀figures.

The findings are discussed in terms of the nature of the surfaces of the powder particles, moisture sorption phenomena and factors such as powder bed permeability and water penetitration lates.     

Content Uniformity of Ethinyldestradiol Tablets 10 μG: Effect of Variations in Processing on the Homogeneity After Dry Mixing and After Tableting

Abstract

The effect of numerous processing factors such as mixer geometry and design, power input, time of dry and wet mixing on the content uniformity of tablets containing potent drugs have been studied. Cohesive drug powders and excipients have been used.

Results show that pharmaceutically acceptable hamageneity is achieved after dry mixing far 7 hours in the Lödige-Marton mixer. It is shown that there is no significant improvement of homogeneity on increasing the time of wet mixing in excess of 5 minutes, and the rate of breakdown of the drug agglomerates and dispersion of individual particles, under the experimental conditions, is very slow. The high energy input exerted by ball milling markedly improves the homogeneity of the powder mixes and the content uniformity of tablets. After 15 minutes of dry mixing, the state of homogeneity of the powder mix containing cohesive drug powder in minute amounts in cohesive excipient is not influenced by the type of mixer.     

Surface Characterisation df Sucrose and Antibiotics Powder Mixes with Relevance to Mixing Theories

Adhesional ordered mixing is not applicable in real systems because ordered interaction between drug and excipient particles can not be achieved. In contrary, Interactive Mixture approach is more applicable because it allows the powder mixtures to be described according to the state of homogeneity achieved which is dependent on mixing variables.

Surface characteristics of powder mixture particles are important to study in order to understand the interparticulate interactions between drug and excipient particles.

Indentations on excipient particles act as mechanical entrapment sites for drug particles which result in areas containing highly localised drug content. Consequently, the state of homogeneity of powder mixtures is possibly affected. Furthermore, the release of particles which are entrapped will be different from those held by interparticulate forces on the plain surfaces of excipient particles. This is particularly important when the excipient particles are insoluble and drug particles are poorly soluble.     

Effect of Granulating Method on Content Uniformity and Other Physical Properties of Granules and their Corresponding Tablets. II

Various properties of dexamethasone and sulfadiazine granules and tablets prepared by microgranulation, slugging, wet granulation and direct compression were compared.

The dexamethasone tablets showed comparable disintegration rates by all methods. The sulfadiazine tablets prepared by slugging did not meet the USP XIX limit, whereas those by microgranulating were satisfactory.

It was found that granule-homogeneity was not only dependent on the particle size and distribution, but also dependent on the granulating method. For either drug, the microgranulating procedure gave the best weight and content uniformity.     

Carboxymethylstarches in Wet Granulation

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     

Use of Statistical Experimental Design in Laboratory Scale Formulation Optimisation and Progression to Plant Scale

The objective of these studies was to optimise the formulation of a dry powder blend to be filled into hard gelatin capsules and progress the product to plant production. The blend was to contain two active compounds (500mg active A and lOmg active B). Preliminary work had limited the independent formulation variables to levels of filling aid, glidant and lubricant. The effects and interactions of the independent variables were assessed using an augmented factorial experimental design demanding the examination of 31 formulations at small scale (less than 3kg). Critical dependent variables identified were blend homogeneity and flow, capsule weight variation and active dissolution rate.

The study plan was to assess blend flow and active dissolution using formulations manufactured at laboratory scale (less than 3kg), select the optimum formulation, confirm the data and determine blend homogeneity at development scale (upto 30kg) and progress to pilot plant production (250kg).

Statistical software was employed to fit response surfaces to optimisation data and generate 3-dimensional plots which were used to assess interactions of excipients and effects on dependent variables. From the 3-dimensional plots it was possible to estimate maxima and minima on the response surfaces enabling selection of optimum combinations of excipients. Using this technique a formulation has been devised which has now been successfully manufactured at development and plant scale. Results obtained at laboratory, development and plant scale were compared and found to be not significantly different.

A comparison of estimated resource expenditure indicated that a conventional approach would have required approximately 350 man hours less than the statistical approach. However, using a conventional approach there is a higher risk of production batch failure, rework or troubleshooting exercises resulting in estimated equivalent losses of 350, 250, and 100 man hours respectively.

The statistical approach is proposed as an aid to formulation optimisation and has several advantages in providing an improved data base, ensuring product robustness, giving higher quality assurance and facilitating troubleshooting. In addition, careful experimental design permits accurate resource estimation and allocation with known gains.     

Preformulation of five Commercial Celluloses in drug Development: Rheological and Mechanical Behaviour

The physical quality of pharmaceutical powders is one of the main element in quality assurance.

A particular attention must be paid to physical and physico-mechanical properties of materials in order to avoid difficulties due to the variability of physical properties, batch to batch, in industry.

Physical characterization, packing characteristics and tableting behaviour applied to five celluloses are studied.

The Authors insist on the importance of packing properties and on his influence on compacting behaviour.     

Polymorphic Transitions of Carbamazepine During Grinding and Compression

Carbamazepine is a potent anticonvulsivant, but, irregular plasma levels are noticed. The variability of therapeutic efficiency can be attributed to interindividual sensibility, chronobiologic effect, but also to rates of dissolution which can differ when polymorphs are induced by technologic operations.

Several crystalline forms of Carbamazepine have been characterized. As for us, we have studied three crystalline modifications which can be found in commercialized galenic forms: the most usual beta form, the alpha form and the dihydrate.

The aim of this work was to investigate:

- the behaviour of these three crystalline forms during compression

- the possibility of crystalline structural changes under grinding and tabletting conditions. Indeed, polymorphous transformations may occur during technologic operations such as grinding or compression owing to the increase of internal energy.

Grinding was performed in a ball mill for 15 and 60 minutes. Compression was carried out using an instrumented single punch machine. The different parameters of compression, and hardness of resulting tablets were investigated.

X Ray diffraction and Differential scanning calorimetry were carried out on the different samples of ground powders and on carefully crushed samples of each batch of tablets.

The results point out at the best compressibility of dihydrate, and the most effective stability of the alpha form. However, the usual beta form remains stable in normal conditions of fabrication and storage.     

Comparison of Disintegrant and Binder Activity of Three Corn Starch Products

This study demonstrates the differences obtained when using different corn starch products as both binder and disintegrant in pharmaceutical tablets. Formulations made with Fluftex W, Tablet White and Purity 21 starches were compared. In addition, Avicel PH101 was used in this study as a benchmark component whose properties are well understood.

Four test formulations containing hydrochlorothiazide were prepared by wet granulation. Starch was incorporated in both powder and paste form. All granulations were found to possess similar traits when evaluated based upon geometric mean diameter, particle size distribution, bulk/tap densities, powder flow rate and surface characteristics.

Tablets prepared from these granulations were shown to be similar when evaluated for degree of friability, weight and content uniformity. All starch formulations disintegrated within 30 seconds and produced similar dissolution profiles. Tablets produced with Avicel, however, were found to exhibit significantly longer disintegration times than the starch formulations. In addition, these tablets displayed a dissolution profile that was significantly different than the starch formulations, particularly during the earlier stages of the dissolution process.

When monitoring compression and ejection forces required to produce tablets of the same degree of hardness (≈6kg), Fluftex W and Tablet White granulations were found to use significantly lower forces than the Purity 21 granulation. This may be indicative of Fluftex W and Tablet White's superiority over Purity 21 in terms of binder capacity.     

Comparison of Disintegrant and Binder Activity of Three Corn Starch Products

This study demonstrates the differences obtained when using different corn starch products as both binder and disintegrant in pharmaceutical tablets. Formulations made with Fluftex W, Tablet White and Purity 21 starches were compared. In addition, Avicel PH101 was used in this study as a benchmark component whose properties are well understood.

Four test formulations containing hydrochlorothiazide were prepared by wet granulation. Starch was incorporated in both powder and paste form. All granulations were found to possess similar traits when evaluated based upon geometric mean diameter, particle size distribution, bulk/tap densities, powder flow rate and surface characteristics.

Tablets prepared from these granulations were shown to be similar when evaluated for degree of friability, weight and content uniformity. All starch formulations disintegrated within 30 seconds and produced similar dissolution profiles. Tablets produced with Avicel, however, were found to exhibit significantly longer disintegration times than the starch formulations. In addition, these tablets displayed a dissolution profile than was significantly different than the starch formulations, particularly during the earlier stages of the dissolution process.

When monitoring compression and ejection forces required to produce tablets of the same degree of hardness (≈6kg), Fluftex W and Tablet White granulations were found to use significantly lower forces than the Purity 21 granulation. This may be indicative of Fluftex W and Tablet White's superiority over Purity 21 in terms of binder capacity.     

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

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

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

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

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

Dissolution properties of direcet compression tablets containing an agglomerated cellulose powder

In previous studies a novel agglomerated cellulose powder was shown to own advantageous properties for direct compression. Due to the favourable particle and powder properties this material has good binding and disintegration ability in direct compression tablets. In this study the dissolution properties of direct compression tablets containing the agglomerated cellulose powder as a fillerbinder were evaluated. Especially the effect of the amount of cellulose, the porosity of tablets, the solubility of drug material and the amount and the amount and mixing method of lubricant, magnesium stearate were studied.

Tablets containing different amounts of cellulose with dicalcium phosphate as a filler and 10 wt % of water soluble sodium tolmetin as a drug were compressed at a constant pressure of 150 MPa. The breaking strength of tablets increased with increasing amounts of agglomerated cellulose powder. However, the dissolution of drug accelerated up to cellulose amount of 50 wt %. This was due to the ability of the agglomerated cellulose powder to enhance the water penetration into powder compact and the loosening of tablet structure, i.e. formation of cracks.

Tablets containing 20 wt % of cellulose material and 10 wt % of drug material were compressed to different porosities. Tablet porosity had no effect on dissolution of poorly water soluble tolfenamic acid. Also the dissolution of water soluble sodium tolmetin was only slightly affected by the porosity of tablets. This supports the suggested disintegrant mechanism of the agglomerated cellulose powder. The expansion of cellulose agglomerates, which have been deformed, under compression, is widely responsible for the disintegration of the tablets. An increase in the amount as well as in the mixing intensity of magncsium stearate decreased the dissolution of sodium tolmetin from tablets containing 20 wt % of agglomerated cellulose. However, the intrinsic wetting and dissolution phenomens were practically unchanged when the amount of magnesium stearate was below 2 wt %. Thus, the retardation of drug dissolution was acceptable at low lubricant concentrations.

The properties of tablets containing the agglomerated cellulose were compared to those containing microcrystalline cellulose. In all cases tablets containing the agglomerated cellulose powder liberated drug clearly faster and more properly than corresponding microcrystalline cellulose tablets.     

“Monitoring Punch Forces and Punch Movements as an AID to Developing Robust Tablet Formulations”

The benefits of commencing the pharmaceutical development program for a new drug entity as soon as practical are obvious. However, the ability to do so is controlled by many factors including limited availability of drug substance and very little information on pharmaceutically relevant properties. It is this data which the formulator must begin to collect as soon as any material becomes available. Establishing the physico-chemical characteristics (often referred to as 'preformulation') covers a wide range of attributes. This paper only considers those which can be investigated by use of instrumented compaction equipment

The first experiments should include establishing the intrinsic compactibility of the compound by preparation of simple compacts of drug substance under controlled conditions and with essentially no additives except die wall lubrication. Irrespective of whether compacts are formed or not, the raw data collected from the instrumentation may be used to give an initial reading of this important property of the material

On completion of these tests on drug substance, the development process then follows a pattern of making simple tablets and testing them for dissolution, strength, content uniformity, etc. Instrumentation can improve the efficiency of this process in several ways by providing information on predominant compaction mechanisms, a predictive capability of strength and maybe even dissolution. It will also create a data base of 'normal' results and a rapid, easy screen for variability

If the work is being carried out on a sophisticated test instrument or simulator, the formulations may be subjected to high speed tabletting cycles in order to obtain a measure of the strain rate sensitivity. Several reports have now shown the effect of strain rate on properties such as tensile strength of tablets and their disintegration time

As more drug substance becomes available a set of experiments designed to identify a commercializable formulation is carried out. This is also an appropriate point to transfer the processing to a rotary tablet press (if not already done), but the conditions must be controllable and precisely known. From these experiments a primary and at least one back-up formulation are identified, including processing conditions as well as composition

The first clinical material, using the preferred formula and manufacturing instructions, can now be made. During the ensuing development phases the emphasis on utilisation of the instrumentation changes, but many of the measurements already referred to, are still useful. Much of the data resulting from the overall program described, can provide an impressive addition to the “Formulation Development” section of any submission!     

Influence of Magnesium Stearate on the Homogeneity of a Prednisone-Granule Ordered Mix

The use of ordered systems has been advocated in the formulation of microdose delivery systems to improve and maintain drug homogeneity during mixing. This study considered the effect of a lubricant such as magnesium stearate on the degree of homogeneity and stability of a preformed prednisone-granule ordered mix. Micronized prednisone was mixed with starch-lactose granules to produce an ordered mix of satisfactory homogeneity. Magnesium stearate in concentrations above and below the theoretical surface saturation of the granule caused negligible change in the degree of homogeneity. Sieve analysis of the mix and subsequent analysis of size fractions for prednisone allowed the prednisone distribution within the mix to be determined. Prednisone was found to be associated with the granules in all the mixes; the magnesium stearate did not compete for the surface adsorption sites and did not dislodge the drug from the granule surface, during mixing and mild demixing conditions. However, a decrease in surface adsorbed prednisone occurred in all mixes (with and without magnesium stearate) under more severe segregating conditions.

Recent research in drug homogeneity studies in microdose tablets has highlighted serious problems in dosage variation¹. Drugs are frequently micronized to improve their release from the solid dosage form. Micronization produces drug particles which are extremely cohesive and interactive. In practice, the adequate mixing of micronized powders with other excipients may be difficult to achieve since this cohesiveness produces aggregation of drug particles and interaction of the drug with the mixer surfaces. In recent years some research effort has been applied to using the interactive nature of drug particles to improve the homogeneity of mixes^2,3. Controlled adsorption of a micronized drug particle onto a carrier particle to produce an “ordered unit” has been shown to minimize segregation within the mix^4,5. Some of the factors affecting the degree of homogeneity of “ordered mixes” have been studied^6,7. However, little research has been conducted on the influence of other excipients on the homogeneity and stability of preformed ordered mixes. A cautionary note on the use of magnesium stearate in ordered mixtures indicated that the lubricant may displace salicylic acid from a sucrose carrier under conditions of segregation⁸. The purpose of this study, therefore, was to evaluate the influence of a third component such as magnesium stearate on the degree of homogeneity and stability of a preformed prednisone-starch lactose granule ordered system during a mixing process.     

Cellulose Acetate Trimellitate Microspheres Containing NSAIDS

Indomethacin and ketoprofen (non-steroidal anti-inflammatory drugs) were incapsulated with cellulose acetate trimellitate, enteric polymer, using a spray drying technique.

Organic solutions of polymer and drug were prepared in different weight ratios and sprayed, achieving drug loaded microspheres.

The obtained spray dried microparticles were characterized in terms of yield of production, shape, size, morphological characteristics and drug content.

The in vitro drug release tests, carried out using a pH change method with a flow-through cell apparatus, show a typical delayed drug release due to the pH-dependent solubility of the polymer.     

A review of current techniques for the evaluation of powder mixing

Blending a mixture of powders to a homogeneous system is a crucial step in many manufacturing processes. To achieve a high quality of the end product, powder mixtures should be made with high content uniformity. For instance, producing uniform tablets depends on the homogeneous dispersion of active pharmaceutical ingredient (API), often in low level quantities, into excipients. To control the uniformity of a powder mixture, the first required step is to estimate the powder content information during blending. There are several powder homogeneity evaluation techniques which differ in accuracy, fundamental basis, cost and operating conditions. In this article, emerging techniques for the analysis of powder content and powder blend uniformity, are explained and compared. The advantages and drawbacks of all the techniques are reviewed to help the readers to select the appropriate equipment for the powder mixing evaluation. In addition, the paper highlights the recent innovative on-line measurement techniques used for the non-invasive evaluation of the mixing performance.     

Examination of Components of Variance for A Production Scale, Low Dose Powder Blend and Resulting Tablets

A study was performed to quantify the contributions of the different components comprising the total variance term observed following the analysis of content uniformity testing of powder blends and tablets. A full scale (400 kg) blend study was performed on a low dose tablet formulation (drug content = 0.13%). Content uniformity samples were pulled from throughout the blender using a pocket type probe thief in a manner which allowed the blend to be assessed for both homogeneity and sample to sample variability at a given location. Tablets were compressed from the batch and assayed for content uniformity. Sampling error accounted for approximately 75% of the variance observed following analysis of drug content in the powder blends. The estimated total variance for the powder blend was approximately twice that observed for tablets compressed from the mixture. The analytical contribution to the total variance term was minor. The difference between the estimated total variance terms for powder blend and tablets was attributed to the superior sampling efficiency of the tablet press versus the sample thief. The results of the study support the use of wider specifications for powder blends than the tablets compressed from the mixture.