Material Attributes and Their Impact on Wet Granulation Process Performance

Abstract Surface step morphology of three structural modifications of stearic acid, B(mon), B(orth II) and C(mon), was observed by replica method (TEM). The characteristic simple and interlaced patterns were observed for monoclinic and pseudo-orthorhombic polytypes, respectively. The observation on the C crystals which were transformed from B(orth II) or B(mon) enabled to detect two different modes of lattice displacement involved in composite polymorphic-polytypic transformations from B to C. B(mon) → C(mon) was found to be caused by a collective inclination of the molecules within the lamellar plane followed by the deformation of the subcell of the aliphatic chain, keeping the symmetry-axis unchanged. In contrast, B(orth II) → C(mon) occurs via an alternate rotation of the long-chain molecules in the adjacent lamellae around the c -axis of B(orth II) prototype, keeping the subcell arrangements unchanged. This means that the polytypic structure of a double-layer type was not preserved during the composite B(orth II) → C(mon) transformation. This peculiarity was discussed in terms of the interlamellar instability of a postulated double-layered polytype of the C polymorph.

Spironolactone is a drug derived from sterols that exhibits an incomplete oral absorption due to its low water solubility and slow dissolution rate. In this study, formulations of spironolactone with four disintegrants named as croscarmellose sodium, crospovidone, sodium starch glycolate and microcrystalline cellulose II (MCCII) were conducted. The effect of those disintegrants on the tensile strength, disintegration time and dissolution rate of spironolactone-based compacts was evaluated using a factorial design with three categorical factors (filler, lubricant, and disintegrant). The swelling values, water uptake and water sorption studies of these disintegrants all suggested that MCCII compacts disintegrate by a wicking mechanism similar to that of crospovidone, whereas a swelling mechanism was dominant for sodium starch glycolate and croscarmellose sodium. The disintegration time of MCCII and sodium starch glycolate remained unchanged with magnesium stearate. However, this lubricant delayed the disintegration time of crospovidone and croscarmellose sodium. MCCII presented the fastest disintegration time independent of the medium and lubricant employed. The water sorption ratio and swelling values determined sodium starch glycolate followed by croscarmellose sodium as the largest swelling materials, whereas crospovidone and MCCII where the least swelling disintegrants. The swelling property of sodium starch glycolate and croscarmellose sodium was strongly affected by the medium pH. The disintegration time of spironolactone compacts was faster when starch was used as a filler due to the formation of soft compacts. In this case, the type of filler employed rather than the disintegrant had a major effect on the disintegration and dissolution times of spironolactone.

Microcrystalline cellulose (MCC) was pulverized with a vibrational rod mill. The degree of crystallinity of MCC decreased from 65.5 to 12.1% with pulverization time due to mechanochemical effect. Pulverized MCCs were compressed at 155.6 MPa using a compression test apparatus, and the two parameters relating to compactability, the B value and yield pressure, were calculated using a Heckel plot. These values were lowered as the degree of crystallinity of MCC became smaller. These results suggest that the crystal region and the amorphous region in MCC particles may be mainly fractured and deformed plastically during compression, respectively. Then the dissolution test was performed for the acetaminophen-MCC (10:90) tablets. Dissolution profiles showed an interesting phenomenon, namely, the dissolution rate of acetaminophen from MCC tablet decreased when the degree of crystallinity of MCC was in the range from 65.5 to 37.6%, however, it increased markedly when the degree of crystallinity of MCC was in the range from 25.8 to 12.1%. The amount of water absorbed into tablets changed in accord with the dissolution rates of acetaminophen from tablets. The dissolution data indicate that drug release can be modified by changing the degree of crystallinity of MCC.

Polyplasdone of different particle size was used to study the sorption, desorption, and distribution of water, and to seek evidence that larger particles can internalize water. The three samples were Polyplasdone® XL, XL-10, and INF-10. Moisture sorption and desorption isotherms at 25 °C at 5% intervals from 0 to 95% relative humidity (RH) were generated by dynamic vapor sorption analysis. The three products provided similar data, judged to be Type III with a small hysteresis that appears when RH is below 65%. An absent rounded knee in the sorption curve suggests that multilayers form before the monolayer is completed. The hysteresis indicates that internally absorbed moisture is trapped as the water is desorbed and the polymer sample shrinks, thus requiring a lower level of RH to continue desorption. The fit of the Guggenheim-Anderson-de Boer (GAB) and the Young and Nelson equations was accomplished in the data analysis. The W(m), C(G), and K values from GAB analysis are similar across the three samples, revealing 0.962 water molecules per repeating unit in the monolayer. A small amount of absorbed water is identified, but this is consistent across the three particle sizes.

<h2>ABSTRACT</h2> The polymorphic and/or pseudo-polymorphic phase transformation of Drug Z API, from Form I to Form II, occurs during the wet granulation step. It was observed that dissolution of the tablets slowed down under certain manufacturing conditions. Factors responsible for the slowdown in tablet dissolution were investigated in this study. Two levels of shear during premixing and two wet granulation drying temperatures were investigated by measuring the dissolution profiles of the tablets. The interaction between API and excipients was examined using differential scanning calorimetry and X-ray powder diffraction. When stearic acid was present with Form I as the starting material in the formulations, the dissolution slowdown was significant under the conditions of higher shear during premixing or higher drying temperature. However, there was little impact of lower shear premixing or lower drying temperature. When Form I was replaced with Form II, the slowdown in dissolution was mainly observed with higher drying temperature. The tablet dissolution slowdown was due to the interaction between Form II and stearic acid that facilitated the formation of Form I. The transformation back to the Form I material reported here may be classified as a thermal-mechanical facilitated PIT and represents a new subclass of the phenomena. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3849–3862, 2010

Abstract A full factorial experimental design was employed to investigate the effects of mode of disintegrant incorporation and concentration in wet-granulated paracetamol tablets manufactured by topspray fluid-bed. Disintegrants (croscarmellose sodium, sodium starch glycolate, or crospovidone) were incorporated either intragranularly, extragranularly, or distributed equally between the two phases. The results were analysed by a general quadratic equation and response surfaces generated. On examining the results for dissolution studies the combined mode resulted in significantly faster dissolution rates than did the extragranular mode which, in turn, was superior to the intragranular mode of inclusion. These results were reflected in the disintegration studies where the combined mode exhibited the shortest disintegration times for all the disintegrants. Tablet crushing strength was not affected by the mode of incorporation of concentration of the disintegrants. Main as well as interaction effects between the types, mode of incorporation and percent disintegrant employed were significant (P &amp;lt; 0·05) for disintegration time and percent release at 15 min. Croscarmellose sodium exhibited the shortest while crospovidone displayed significantly (P &amp;lt; 0·05) longer disintegration times. Formulations containing crospovidone did not meet official compendial (USP XXII) requirements of 80% in 30 min. In general, croscarmellose sodium and sodium starch glycolate were found to be less sensitive to the mode of incorporation than crospovidone.

The production of granules by wet granulation in a fluidized bed was assessed according to two statistical techniques to identify the most relevant factors that affect the quality of the granules. The statistics used include Canonical Analysis and Cluster Analysis. The factors studied, according to a center of gravity design, included the solubility of a model drug, different grades of polyvinylpirrolidone (PVP), the polarity and the rate of administration of the granulation solution, the atomizing air pressure, the inlet air pressure and rate. The properties of the granules considered were the yield, the assay of the drug, the size, the densities (true, bulk and tapped), the friability, the flowability and one compressibility index. Statistical analysis of the factors evaluated has shown that the solubility of the materials and the pressure of the atomizing air in the nozzle were the most critical parameters affecting the quality of the granules. Less relevant were the granulation solution and the grade of PVP. The properties of the granules that best described their quality were the yield and the densities. From the Cluster Analysis it was possible to divide the granules in two clusters, where cluster 1 was identifiable by the yield, the assay, the flowability, and the friability, whereas cluster 2 was better identified by the size of the granules.

Abstract The interfacial works of cohesion, adhesion, interaction parameters and spreading coefficients have been calculated for paracetamol granulated with hydroxypropyl methylcellulose, acacia, polyvinyl pyrrolidone and starch using literature values of surface free energies. In general, the predictions made regarding film formation, granule morphology and failure processes are consistent with literature data. Correlations have been found between the spreading coefficient of the binder over the substrate and actual experimental measurements of granule friability, tablet strength and tablet capping. The shape and complexity of the relationships can be further explained on the basis of the relative changes in binder cohesion.

Pharmaceutical tablets are manufactured through a series of batch steps finishing with compression into a form using a tablet press. Lubricants are added to the powder mixture prior to the tabletting step to ensure that the tablet is ejected properly from the press. The addition of lubricants also affects tablet properties and can affect the behavior of the powder mixture. The objective of this research was to investigate the effect of lubricants on powder flowability as flowability into the tablet press is critical. Four lubricants (magnesium stearate, magnesium silicate, stearic acid, and calcium stearate) were mixed, in varying amounts, with spray-dried lactose. In addition, magnesium stearate was also mixed with placebo granules from a high-shear granulator. Measurements based on avalanche behavior indicated flowability potential and dynamic density and were more sensitive to changes in the mixture and provided a more accurate and reproducible indication of flowability than traditional static measurements. Of the tested lubricants, magnesium stearate provided the best increase in flowability even in the low amounts commonly added in formulations.

Abstract The agglomeration of a powder mixture which is commonly used to make granules containing enzyme was examined in a high shear mixer granulator of the Lodige type. The validity and extension of current granulation theory for practical high shear granulation was investigated. The effects of process variables such as the amount of binder liquid, choppe impact, binder viscosity and temperature on the granulation were in agreement with the theory. The onset of the different granulation mechanisms (nucleation, compaction, coalescence, and crushing and layering) was demonstrated.

The aim of the present investigation was to develop controlled release (C.R.) matrix tablet formulations of rifampicin and isoniazid combination, to study the design parameters and to evaluate in vitro release characteristics. In the present study, a series of formulations were developed with different release rates and duration using hydrophilic polymers hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC). The duration of rifampicin and isoniazid release could be tailored by varying the polymer type, polymer ratio and processing techniques. Further, Eudragit L100-55 was incorporated in the matrix tablets to compensate for the pH-dependent release of rifampicin. Rifampicin was found to follow linear release profile with time from HPMC formulations. In case of formulations with HPC, there was an initial higher release in simulated gastric fluid (SGF) followed by zero order release profiles in simulated intestinal fluid (SIFsp) for rifampicin. The release of isoniazid was found to be predominantly by diffusion mechanism in case of HPMC formulations, and with HPC formulations release was due to combination of diffusion and erosion. The initial release was sufficiently higher for rifampicin from HPC thus ruling out the need to incorporate a separate loading dose. The initial release was sufficiently higher for isoniazid in all formulations. Thus, with the use of suitable polymer or polymer combinations and with the proper optimization of the processing techniques it was possible to design the C.R. formulations of rifampicin and isoniazid combination that could provide the sufficient initial release and release extension up to 24 h for both the drugs despite of the wide variations in their physicochemical properties.

The purpose of this study is to identify critical physicochemical properties of hydroxypxropyl methylcellulose (HPMC) that impact the dissolution of a controlled release tablet and develop a strategy to mitigate the HPMC lot-to-lot and vendor-to-vendor variability. A screening experiment was performed to evaluate the impacts of methoxy/hydroxypropyl substitutions, and viscosity on drug release. The chemical diversity of HPMC was explored by nuclear magnetic resonance (NMR), and the erosion rate of HPMC was investigated using various dissolution apparatuses. Statistical evaluation suggested that the hydroxypropyl content was the primary factor impacting the drug release. However, the statistical model prediction was not robust. NMR experiments suggested the existence of structural diversity of HPMC between lots and more significantly between vendors. Review of drug release from hydrophilic matrices indicated that erosion is a key aspect for both poorly soluble and soluble drugs. An erosion rate method was then developed, which enabled the establishment of a robust model and a meaningful HPMC specification. The study revealed that the overall substitution level is not the unique parameter that dictates its release-controlling properties. Fundamental principles of polymer chemistry and dissolution mechanisms are important in the development and manufacturing of hydrophilic matrices with consistent dissolution performance.

Abstract A method has been developed for the frictional assessment of powder lubricants using a shear-box tester similar to that employed by Jenike. One commercial magnesium stearate, three high-purity magnesium stearates and three high-purity magnesium palmitates were assessed using this method. Powders with a well-ordered crystal structure and particle shape have a lower initial maximum coefficient of friction μa. The difference between μa and μb, the equilibrium dynamic friction coefficient, gives an indication of lubricant film-forming propensity. The basic friction equation is obeyed by the powders for most of the load range studied but deviates slightly approaching zero normal load.

Lubrication plays a key role in successful manufacturing of pharmaceutical solid dosage forms; lubricants are essential ingredients in robust formulations to achieve this. Although many failures in pharmaceutical manufacturing operations are caused by issues related to lubrication, in general, lubricants do not gain adequate attention in the development of pharmaceutical formulations. In this paper, the fundamental background on lubrication is introduced, in which the relationships between lubrication and friction/adhesion forces are discussed. Then, the application of lubrication in the development of pharmaceutical products and manufacturing processes is discussed with an emphasis on magnesium stearate. In particular, the effect of its hydration state (anhydrate, monohydrate, dihydrate, and trihydrate) and its powder characteristics on lubrication efficiency, as well as product and process performance is summarized. In addition, the impact of lubrication on the dynamics of compaction/compression processes and on the mechanical properties of compacts/tablets is presented. Furthermore, the online monitoring of magnesium stearate in a blending process is briefly mentioned. Finally, the chemical compatibility of active pharmaceutical ingredient (API) with magnesium stearate and its reactive impurities is reviewed with examples from the literature illustrating the various reaction mechanisms involved.

The effect of variation in the degree of cross-linkage and extent of carboxymethylation on the disintegration and dissolution properties of sodium starch glycolate has been examined. Samples of sodium starch glycolate were evaluated for particle size distributions and bulk and tapped densities. The bulk powders were also tested for sedimentation volumes, water uptake, and bulk swelling. Direct compression formulations containing aspirin and hydrochlorothiazide and varying concentrations of the modified starches were tableted on a rotary tablet press and evaluated for weight variation, hardness, disintegration, and dissolution. The results indicate that relatively small changes in molecular structure can cause substantial modification of disintegrant properties and suggest that the specifications for one commercially available sodium starch glycolate are within optimal specifications for both cross-linkage and degree of substitution.

Abstract The effects of moisture on the structure of two commercial (batch A and batch B) and one pure grade (batch C) of magnesium stearate have been examined by using differential scanning calorimetry (DSC), thermogravimetry (TG), X-ray powder diffractometry (XRD) and thermomicroscopy (HSM). The results suggest that the role of water is different in both of the commercial batches. Powder A showed a two-stage mass loss at temperatures between 25°C and 100°C indicating that the water present was tightly bound. The scans from batch B exhibited a continual mass decrease indicating that the moisture present was more loosely bound. With high purity magnesium stearate (batch C) water was bound in the ratio of two molecules to every one of the fatty acid salt. During storage to hydrate at 76% RH and 93% RH, powder A became more crystalline while powder B remained amorphous. Magnesium stearate dihydrate exhibited no tendency to form a trihydrate or higher hydrated forms. A short review of previous studies on magnesium stearate is given in the Introduction.

The disintegration and dissolution of acetaminophen tablets containing sucrose and Ac-Di-Sol/Primojel was significantly different between acidic and neutral media. The purpose of this study was to investigate the mechanism of this phenomenon and to propose a way of reducing the dissolution difference between the two media. Tablets of different combinations of active ingredient, sucrose, and Ac-Di-Sol/Primojel were prepared and their dissolution in various media was evaluated. The dissolution differences were found to be largely related to the hydrophobicity of the active ingredient and pH difference of the two media. This difference was even more evident under the condition where acetaminophen, sucrose, and Primojel were combined. The dissolution difference was therefore attributed to the depressed function of Primojel in the acidic medium, the stronger binding of sucrose, the hydrophobicity of the active ingredient and pH difference of the two media. Increasing the concentration of Primojel or incorporating the surfactant in the tablet can thus greatly decrease the dissolution difference between acidic and neutral media.

The effect of the physicochemical properties of binders on the strength of agglomerates prepared by the wet method was investigated using untreated and surface trimethylsilylated glass beads as model powders. The crushing test of granules and the bending test of molded tablets were carried out in order to estimate the strength of the agglomerates. A quantitative approach based on the work of Rumpf et al. was attempted to obtain the strengths between two contacting particles. The calculated values were in fair agreement with those obtained by the separation test using two big balls. In all the systems, the agglomerates prepared from surface treated glass were weaker in strength than those from untreated glass. In conclusion, it was apparent that the strength of an agglomerate was related both to the wetting of a particle by a binder solution and to the binder cohesion.

This study investigated the influence of the degree of polymerization (DP) of cellulose materials (microcrystalline cellulose [MCC]) on some powder properties and the compression behavior of these materials. The DP was determined by measurements of viscosity (H). The weight average of molecular weight and the weight average of the different DPs were investigated after MCC was modified to cellulose tricarbanilate by light scattering measurements. The DP showed a remarkable influence on the physicochemical properties of the cellulose materials and, consequently, on the behavior of these materials during compression. MCC types with a high DP value showed greater water absorption than the types with a low DP value. No relevant relationship between the crystallinity index and the DP could be observed. DP 190 showed lower compactibility and compressibility parameters than DP 244 and 299. No significant differences could be observed between DP 244 and 299 when the same particle size fraction was compressed. Furthermore, the compressibility was increased by increasing the DP.

AbstractStudies of different particle size grades of cross linked polyvinylpolypyrrolidone (Polyplasdone G.A.F. Corporation) In direct compression tablet formulations show that Increase in mean particle size enhances powder flow, disintegration and dissolution although hardness and friability were slightly better for tablets made from the finer grades. The disintegrant exhibits powerful disintegrant action at low concentrations. It should probably be rarely, if ever, necessary to use more than five per cent in a tablet in order to achieve rapid dissolution. It appears that the use of polyvinylpolypyrrolidone (P.V.P.P.) as a tablet disintegrant at high concentrations may be self limiting since certain properties such as powder flow, tablet weight variation, hardness and friability start to reach unacceptable levels at high disintegrant concentrations. Data presented in this paper indicates that tablets con-taining acetylsalicylic acid or multi-vitamins can be very effec-tively formulated using P.V.P.P. as ...

The objective of the current work was to study an observed incompatibility between croscarmellose sodium and basic excipients in a tablet formulation. Significant dissolution slowdown was observed for alkaline tablet compositions of an acid-labile drug containing croscarmellose sodium (CCS) as a disintegrant. The severity of the dissolution slowdown was directly proportional to both the degree of alkalinity and the level of CCS in the tablet formulation. It is postulated that the ester cross-links in CCS were partially or fully hydrolyzed under basic conditions (pH values >9) forming by-products of increased water solubility. This increase in the level of water-soluble polymer can lead to the formation of a viscous barrier in the tablet upon moisture uptake, thus slowing down its dissolution. The dissolution slowdown was not observed for a similar alkaline tablet preparation containing crospovidone as a disintegrant.

Pharmaceutical excipients are essential components of most modern dosage forms. Although defined as pharmacologically inert, excipients can be thought of as the true enablers of drug product performance. Unintentional variability in the properties of the excipients may be unavoidable, albeit minimizable. The variability may originate from the source, the excipient-manufacturing process, or during the manufacturing of dosage forms. Excipient variability may have a range of influences on their functionality and performance in the dosage form. A better understanding of these influences on the critical quality attributes of the final product is of prime importance. Modern analytical tools provide a significant assistance in characterizing excipient variability to achieve this understanding. The principles and concepts of Quality-by-Design, process analytical technology, and design space, provide a holistic risk-based approach toward manufacture and application of excipients in pharmaceutical formulations. The International Pharmaceutical Excipients Council (IPEC) has developed guidelines for proper selection, use, and evaluation of excipients in pharmaceutical products.

The particle size of HPMC is a critical factor that can influence drug release rate from hydrophilic matrix systems. Percolation theory is a statistical tool which is used to study the disorder of particles in a lattice of a sample. The percolation threshold is the point at which a component is dominant in a cluster resulting in significant changes in drug release rates. Mini-tablets are compact dosage forms of 1.5-4 mm diameter, which have potential benefits in the delivery of drug to some patient groups such as pediatrics. In this study, the effect of HPMC particle size on hydrocortisone release and its associated percolation threshold for mini-tablets and tablets was assessed. For both mini-tablets and tablets, large polymer particles reduced tensile strength, but increased the drug release rate and the percolation threshold. Upon hydration, compacts with 45-125 μm HPMC particles formed a strong gel layer with low porosity, reducing hydrocortisone release rates. In comparison, faster drug release rates were obtained when 125-355 µm HPMC particles were used, due to the greater pore sizes that resulted in the formation of a weaker gel. Using 125-355 µm HPMC particles increased the percolation threshold for tablets and to a greater extent for mini-tablets. This work has demonstrated the importance of HPMC particle size in ER matrices, the effects of which are even more obvious for mini-tablets.

In this study the effect of different vessel wall materials on the granule size distributions obtained during high-shear granulation of different materials is investigated. The distributions obtained in glass and stainless steel vessels differ from those obtained in PMMA (polymethyl methacrylate) and PTFE (polytetrafluoroethylene) vessels. The high contact angle of PMMA forces all liquid immediately into the more easily wetted powder bed. In this vessel a fast liquid absorbing powder nucleates in the droplet controlled regime, leading to a narrow particle size distribution. In a vessel with a low contact angle (glass or stainless steel) a liquid layer can be formed on the wall surface. This liquid causes an inhomogeneous distribution of liquid over the powder bed; a broader granule size distribution is the result. With a powder that slowly absorbs liquid, local overwet areas can be created, resulting in large granules. This results in broader granule size distributions as well. In conclusion; the contact angle of the vessel material and the wetting rate of the powder used determine the granule growth process and the resulting granule size distribution.

Celecoxib has extremely poor aqueous wettability and dispersibility. A dispersibility method was developed to study the effects of formulation excipients and processing methods on wetting of celecoxib. In this method, a tablet or powder was placed in water and the turbidity of the resulting "dynamic" suspension was measured. Higher turbidity values reflect better dispersibility. Results show that wet granulation facilitates better drug dispersion than does dry granulation or direct compression. Results from a screening formulation statistical design of experiments (DOE) show that sodium lauryl sulfate (SLS), an anionic surfactant, gives higher celecoxib dispersibility than polysorbate 80, a neutral surfactant. Polyplasdone XL as a disintegrant results in better celecoxib dispersibility than sodium starch glycolate. The binder Kollidon 30 leads to better dispersibility, but slower disintegration than Kollidon 12. Jet-milling celecoxib with excipients not only improves dispersibility of the drug but also the ease of material handling. The method of microcrystalline cellulose addition does not significantly impact tablet properties. The effect of critical formulation variables on the wettability of celecoxib was further examined in prototype formulations. It is found that ionic surfactant resulted in better dispersibility than a neutral surfactant, probably due to charge dispersion. Kollidon 30 gives better drug dispersion than hydroxypropylmethyl cellulose and hydroxypropyl cellulose. This may be explained through a surface energy calculation, where the spreading coefficients between Kollidon 30 and celecoxib indicate formation of open porous granules in which pores can facilitate water uptake. The mode of disintegrant addition also impacts dispersibility of the drug. Dense granules were formed when the disintegrant, Polyplasdone, was added intra-granularly. As the extra-granular portion of the disintegrant increases, the dispersibility of the drug increases as well. The drug initial dispersibility (turbidity at 5 min during the dispersibility test) increases as the tablet porosity increases. A 3-factor face-centered experimental design was conducted to optimize the levels of surfactant (SLS), binder (Kollidon 30) and disintegrant (Polyplasdone). Within the range that was studied, the dispersibility of micronized drug increases as the amount of SLS and Kollidon 30 increases. The level of Polyplasdone has no significant impact on the dispersibility of micronized drug; however, higher levels of Polyplasdone lead to significantly harder tablets.

Tablet disintegration can be influenced by several parameters, such as storage conditions, type and amount of disintegrant, and relative tablet density. Even though these parameters have been mentioned in the literature, the understanding of the disintegration process is limited. In this study, water uptake and force development of disintegrating tablets are analyzed, as they reveal underlying processes and interactions. Measurements were performed on dibasic calcium phosphate tablets containing seven different disintegrants stored at different relative humidities (5-97%), and on tablets containing disintegrants with different mechanisms of action (swelling and shape recovery), compressed to different relative densities. Disintegration times of tablets containing sodium starch glycolate are affected most by storage conditions, which is displayed in decreased water uptake and force development kinetics. Disintegration times of tablets with a swelling disintegrant are only marginally affected by relative tablet density, whereas the shape recovery disintegrant requires high relative densities for quick disintegration. The influence of relative tablet density on the kinetics of water uptake and force development greatly depends on the mechanism of action. Acquired data allows a detailed analysis of the influence of storage conditions and mechanisms of action on disintegration behavior.

Abstract The structure, dehydration behaviour, and particle characteristics of the two currently available commercial brands of unmilled dicalcium phosphate dihydrate (DCPD) for direct compression, Emcompress and DiTab, were studied. The two brands have very similar properties, differing significantly only in intraparticle porosity. As a consequence, their compression and flow properties are effectively identical. The characteristics of Emcompress and DiTab were compared with those of two DCPD powders, Calipharm (whose properties are typical of milled DCPD preparations) and Kyowa (whose properties are in many respects atypical). It is concluded that the processing undergone by unmilled DCPD for direct compression does not cause major changes in crystal structure, mechanical and surface properties with respect to typical powders. However, there are considerable differences in dehydration behaviour, which can probably be attributed to the larger mean particle size and different particle structure of the direct compression preparations.

The ICH quality vision introduced the concept of quality by design (QbD), which requires a greater understanding of the raw material attributes, of process parameters, of their variability and their interactions. Microcrystalline cellulose (MCC) is one of the most important tableting excipients thanks to its outstanding dry binding properties, enabling the manufacture of tablets by direct compression (DC). DC remains the most economical technique to produce large batches of tablets, however its efficacy is directly impacted by the raw material attributes. Therefore excipients’ variability and their impact on drug product performance need to be thoroughly understood. To help with this process, this review article gathers prior knowledge on MCC, focuses on its use in DC and lists some of its potential critical material attributes (CMAs).

The behaviour of two types of magnesium stearate with different specific surface areas on granule particles was examined. The magnesium stearate concentration was measured with an energy-dispersive X-ray fluorescence analyser. Different measurement procedures were used to investigate the properties of the two types of magnesium stearate when using different blending times and rotation speeds. Correlations were found between the specific surface area of the magnesium stearate, the blending time, the rotation speed and the specific surface free energy of the excipients. If magnesium stearate has a high specific surface area it shows higher adhesion work and is able to create a very thin homogeneous layer on the surface of the particles. Magnesium concentration was detected with the energy-dispersive X-ray fluorescence analyser. Based on the X-ray investigation the optimum blending time and rotation speed can be determined.

Abstract The characteristics of four brands of microcrystalline cellulose manufactured in Finland, India, Ireland and Japan have been determined; all four were nominally similar to Avicel PH 101. There were significant differences in lignin content, hemicellulose sugars content and composition, presence or absence of cellulose II, enthalpy of immersion, particle size and flow properties. Crystallinity correlated with water-cellulose interaction, and particle size with flow properties.

Abstract Four tablet disintegrants: a relatively insoluble sodium carboxymethyl cellulose, casein formaldehyde, calcium carboxymethyl cellulose and a cross-linked polyvinylpyrrolidone have been evaluated. Three widely used disintegrants, sodium carboxymethyl cellulose, sodium starch glycolate and a cation exchange resin were included for comparison. The effect of compressional pressure on the disintegration and dissolution behaviours of a soluble and an insoluble system containing different disintegrants was examined. The results show that disintegrant type can have a pronounced effect upon the relationship between compressional pressure and dissolution efficiency. The significance of this relationship is discussed in terms of the properties of disintegrants and the differing mechanisms by which they act.

The effect of anhydrous lactose particle size distribution on its performance in the wet granulation process was evaluated. Three grades of anhydrous lactose were used in the study: "as is" manufacturer grade and 2 particle size fractions obtained by screening of the 60M lactose. Particle growth behavior of the 3 lactose grades was evaluated in a high shear mixer. Compactibility and porosity of the resulting granules were also evaluated. A uniaxial compression test on moist agglomerates of the 3 lactose grades was performed in an attempt to explain the mechanism of particle size effect observed in the high shear mixer. Particle growth of anhydrous lactose in the high shear mixer was inversely related to the particle size of the starting material. In addition, granulation manufactured using the grade with the smallest particle size was more porous and demonstrated enhanced compactibility compared with the other grades. Compacts with similar porosity and low liquid saturation demonstrated brittle behavior and their breakage strength was inversely related to lactose particle size in the uniaxial compression test, suggesting that material with smaller particle size may exhibit more pronounced nucleation behavior during wet granulation. On the other hand, compacts prepared at higher liquid saturation and similar compression force exhibited more plastic behavior and showed lower yield stress for the grade with smallest particle size. The lower yield stress of compacts prepared with this grade may indicate a higher coalescence tendency for its granules during wet granulation.

Magnesium stearate was mixed with different sieved fractions (80–180, 180–250, 250–350 μm) of microcrystalline cellulose (Avicel PH 102). The influence of mixing time on crushing strength and disintegration of tablets compressed from these mixtures were studied. The disintegration time increased and the crushing strength decreased with increasing particle size of the Avicel fractions. When magnesium stearate is mixed with table excipients the size of these materials could have an effect on the deterioration of the tablet properties as a function of mixing time.

Abstract Hydroxypropyl methylcellulose 2208 (HPMC 2208) was used as the rate-controlling polymer in a naproxen controlled release tablet formulation. A study was undertaken to correlate the physicochemical properties (e.g., molecular weight, particle size, hydroxypropyl and methoxy content, etc.) of different lots of HPMC 2208 from two suppliers with in vitro drug release. All lots had varying chemical compositions but identical particle size sieve fractions. The dissolution of tablets manufactured with seven lots of HPMC 2208 were evaluated. The results indicated that the hydroxypropyl content of HPMC 2208 is the major factor that controls drug release. Irrespective of the supplier, drug release was directly proportional to the hydroxypropyl content. Since the dissolution performance of this product was dependent on the chemical composition of the HPMC 2208, which has wide compendial specifications, the results indicate that pharmaceutical manufacturers must be aware of the potential consequences of either lot to lot variability or changing suppliers of HPMC 2208 without proper characterization. Furthermore, this work demonstrated that compendial specifications for this excipient may be too broad for certain types of dosage forms.

Abstract Dicalcium phosphate dihydrate (Emcompress) and anhydrous dicalcium phosphate (Anhydrous Emcompress) for direct compression were compared as regards particle size distribution and flow properties, which were found to be similar for the two products, and microporous structure and compression properties, which differed markedly. Specifically, intraparticular porosity and mean yield pressure of the anhydrous product were greater than for the dihydrate. Several properties of compacts of both products were also compared: compacts of the anhydrous phosphate disintegrated much more rapidly in distilled water than those of the dihydrate, which was attributed to the greater porosity of the former compacts.

Abstract The physical properties of cast films of four polymers, which are used as binders in tableting, have been determined. Films were equilibrated at different relative humidities and tested both in tension, at three rates of strain, and by the use of indentation to determine creep compliance and hardness of the film under load. Granules and compacts have also been made using the four polymers as binders and the properties of these have been measured. One of the polymers, starch, formed a paste that was difficult to mix adequately. With the other three polymers a positive correlation was found between compact crushing strength and the creep compliance, the ultimate tensile strength and the elongation at fracture of the cast films. A negative correlation was found between the compact crushing strength and the Brinell Hardness of the films.

Abstract Overmixing of magnesium stearate with granules in the hopper of a capsule filling machine can slow down their dissolution because of coating by magnesium stearate, which acts as a water repellant. This phenomenon was systematically investigated using three active ingredients representing a wide range of solubility in 0.1 N hydrochloric acid, the dissolution medium. The active ingredients were hydrochlorothiazide, an antiviral agent SQ32756 (BV-araU), and aztreonam, with solubilities in 0.1 N hydrochloric acid of 0.6, 5.0 and 12 mg/ml, respectively, at 37°C. When capsules of an aqueous wet granulated formulation containing one of the aforementioned active ingredients, hydrous lactose, pregelatinized starch, microcrystalline cellulose, and 1% w/w magnesium stearate were filled using the MG2 Futura capsule filler, capsules from the latter part of the filling run exhibited significantly slower dissolution compared to those from the beginning. The extent of slowdown in dissolution of the capsules varied depending upon the aqueous solubility of the active ingredient. The slowdown was maximum for hydrochlorothiazide capsules followed by SQ32756 and aztreonam capsules, respectively. Further studies using SQ32756 as the active ingredient indicated that replacement of magnesium stearate in the formulation with other hydrophobic lubricants such as calcium or zinc stearate gave similar results. However, replacement of magnesium stearate with hydrophilic lubricants such as Stear-O-Wet® or sodium stearyl fumarate did not result in a slowing of dissolution. Among the hydrophobic lubricants, magnesium stearate caused the maximum slowdown in dissolution, followed by zinc and calcium stearates, respectively. This observed rank order was correlated to the surface area of these lubricants. Furthermore, optimization of magnesium stearate concentration to 0.25% w/w provided enough lubrication for capsule filling while resulting in a capsule with satisfactory dissolution. Replacement of pregelatinized starch by starch-derived superdisintegrants such as Explotab® or Primojel® also resulted in no slowing of dissolution of capsules, even after overmixing with 1% w/w magnesium stearate. Although the granules overmixed with 1% w/w hydrophobic lubricants exhibited slow down in dissolution when filled into capsules, tablets compressed from these granules dissolved rapidly.

This paper reports the batch-to-batch and vendor-to-vendor variations in the solid-state characteristics of multiple batches of lactose anhydrous from each of three vendors and the subsequent impact of these differences on processability and/or functionality.

Abstract The characteristics of prednisone tablets formed by direct compression with six previously characterized microcrystalline celluloses (MCCs) were studied. MCCs of similar particle size produced tablets with similar mechanical and microstructural properties, but prednisone dissolution rate varied significantly with MCC particle size and chemical composition. When stored under conditions of high relative humidity, all formulations underwent significant changes in mechanical and drug release properties, which is attributed to interaction between MCC and water.

Sieve fractions of α-lactose monohydrate and dicalcium phosphate dihydrate, respectively, suspended in solutions of lactose, were spray dried in order to obtain products with various amorphous lactose contents. The compactibility of the samples appeared to be a function of both the primary particle size and the amount of amorphous lactose. The lactose glass was considered to form a binding layer on the particle surface area. Its efficacy was found to be determined by the size and the consolidation of the particles at lower percentages, whereas the specific properties of fully amorphous spray dried lactose, e.g. its susceptibility to water uptake and magnesium stearate mixing, were brought out especially at high percentages.

The purpose of this study was to gain further understanding of how the substituent heterogeneity of hydroxypropyl methylcellulose, HPMC, affects the polymer release from hydrophilic matrix tablets. The hypothesis was that the heterogeneous substituent pattern facilitated hydrophobic interactions that increased the viscosity and therefore affected the release rate to a major extent. Polymer tablets were prepared from three heterogeneously substituted HPMC batches of the same substituent (2208) and viscosity (100 cps) grade. To elucidate the hypothesis, fractions of both the dissolved polymer and the tablet residue were collected from the dissolution bath and further characterised. The extensive characterisation showed that, although the dissolved bath fraction and the tablet residue had a similar average degree of substitution, the residue was more heterogeneously substituted. It was further revealed that the heterogeneous substituent pattern of the tablet residue facilitated the formation of soluble gel-like components already at room temperature, which increased the viscosity. The viscosity increased by 150% at temperatures correlated to the dissolution bath, and it was thus concluded that the gel-like components grew in size with temperature. Finally, much lower release rates were obtained by tablets composed of the residue compared to tablets composed of the bath fraction, which clarified the hypothesis.

The crystal structures of active pharmaceutical ingredients and excipients should be strictly controlled because they influence pharmaceutical properties of products which cause the change in the quality or the bioavailability of the products. In this study, we investigated the effects of microcrystalline cellulose (MCC) crystallinity on the hydrophilic properties of tablets and the hydrolysis of active pharmaceutical ingredient, acetylsalicylic acid (ASA), inside tablets by using tablets containing 20% MCC as an excipient. Different levels of grinding were applied to MCC prior to tablet formulation, to intentionally cause structural variation in the MCC. The water penetration and moisture absorbability of the tablets increased with decreasing the crystallinity of MCC through higher level of grinding. More importantly, the hydrolysis of ASA inside tablets was also accelerated. These results indicate that the crystallinity of MCC has crucial effects on the pharmaceutical properties of tablets even when the tablets contain a relatively small amount of MCC. Therefore, controlling the crystal structure of excipients is important for controlling product qualities.

Reactive impurities in pharmaceutical excipients could cause drug product instability, leading to decreased product performance, loss in potency, and/or formation of potentially toxic degradants. The levels of reactive impurities in excipients may vary between lots and vendors. Screening of excipients for these impurities and a thorough understanding of their potential interaction with drug candidates during early formulation development ensure robust drug product development. In this review paper, excipient impurities are categorized into six major classes, including reducing sugars, aldehydes, peroxides, metals, nitrate/nitrite, and organic acids. The sources of generation, the analytical method for detection, the stability of impurities upon storage and processing, and the potential reactions with drug candidates of these impurities are reviewed. Specific examples of drug-excipient impurity interaction from internal research and literature are provided. Mitigation strategies and corrective measures are also discussed.

Investigation of the effect of disintegrants on the disintegration time and hardness of rapidly disintegrating tablets (RDTs) was carried out using a quality by design (QbD) paradigm. Ascorbic acid, aspirin, and ibuprofen, which have different water solubilities, were chosen as the drug models. Disintegration time and hardness of RDTs were determined and modeled by executing combined optimal design. The generated models were validated and used for further analysis. Sodium starch glycolate, croscarmellose sodium, and crospovidone were found to lengthen disintegration time when utilized at high concentrations. Sodium starch glycolate and crospovidone worked synergistically in aspirin RDTs to decrease disintegration time. Sodium starch glycolate-crospovidone mixtures, as well as croscarmellose sodium-crospovidone mixtures, also decreased disintegration time in ibuprofen RDTs at high compression pressures as compared to the disintegrants used alone. The use of sodium starch glycolate in RDTs with highly water soluble active ingredients like ascorbic acid slowed disintegration, while microcrystalline cellulose and crospovidone drew water into the tablet rapidly and quickened disintegration. Graphical optimization analysis demonstrated that the RDTs with desired disintegration times and hardness can be formulated with a larger area of design space by combining disintegrants at difference compression pressures. QbD was an efficient and effective paradigm in understanding formulation and process parameters and building quality in to RDT formulated systems.