To investigate the influence of machine operating variables on formulations derived from lactose types in capsule filling: part 2.

This study is the second in a series that examines the characterizing and selection of suitable grades of lactose for capsule formulation development. Based upon the previous study, four grades were selected for further study. The effects of drug load and operational variables on formulations derived from these four lactose types were evaluated for physicochemical and mechanical attributes of plugs and their capsules on an instrumented dosing-disc capsule filling machine (H&H KFM/3) using acetaminophen as a model, highly soluble and poorly compressible drug. The results obtained were as follows: (1) flowability reduced upon increasing drug load; (2) powder bed height (PBH) and compression force (CF) had positive significant effect on plug weight (p < 0.05); (3) ejection force was positively and significantly correlated with increasing speed and CF (p < 0.05); (4) AL capsule plugs had the highest plug crushing force which was followed by DCL15; (5) the crushing strength of plugs made from DCL11 increased with increasing acetaminophen concentration; (6) higher CF had a significant negative impact on acetaminophen release at 15 min time point (p < 0.05); (7) at 10% and 40% drug load, formulations containing AL showed the quickest drug release; and (8) increased drug load had a significant negative impact on the release rate at 15 and 45 min time points (p < 0.05). Overall, the results from this study provides information on risk based assessment of filler selection based on drug load and the range of machine operating variables which will help in defining criteria for meeting key quality attributes for capsule formulation development.

Characterization and selection of suitable grades of lactose as functional fillers for capsule filling: part 1.

The purpose of this work is to characterize thermal, physical and mechanical properties of different grades of lactose and better understand the relationships between these properties and capsule filling performance. Eight grades of commercially available lactose were evaluated: Pharmatose 110 M, 125 M, 150 M, 200 M, 350 M (α-lactose monohydrate), AL (anhydrous lactose containing ∼80% ß-AL), DCL11 (spray dried α-lactose monohydrate containing ∼15% amorphous lactose) and DCL15 (granulated α-lactose monohydrate containing ∼12% ß-AL). In this study, different lactose grades were characterized by thermal, solid state, physical and mechanical properties and later evaluated using principal component analysis (PCA) to assess the inter-relationships among some of these properties. The lactose grades were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray diffraction (XRD), moisture sorption/desorption isotherms, particle size distribution; the flow was characterized by Carr Index (CI), critical orifice diameter (COD) and angle of friction. Plug mechanical strength was estimated from its diametric crushing strength. The first and second principal components (PC) captured 47.6% and 27.4% of variation in the physical and mechanical property data, respectively. The PCA plot grouped together 110 M, AL, DCL11 and DCL15 on the one side of plot which possessed superior properties for capsule formulation and these grades were selected for future formulation development studies (part II of this work).

Application of a novel automatic disintegration apparatus for the development and evaluation of a direct compression rapidly disintegrating tablet.

An automatic disintegration tester was developed and used to explore disintegration mechanism and times of rapidly disintegrating tablets. DT50, the time required for a tablet to decrease in its thickness by half, allowed an unbiased determination of disintegration time. Calcium silicate concentration, Explotab® concentration, DiPac®/Xylitab® ratio as fillers, and compression pressure were evaluated using a central composite model design analysis for their DT50, tensile strength, and friability. Tablets that could reasonably be handled (friability <10%) could be produced. The expansion coefficient (n) and the exponential rate constant (k) for disintegrating tablets, originally measured by Caramella et al. using force kinetics, could be determined from axial displacement data measured directly without the need to assume that disintegration force generation was indicative of changes in tablet volume. The n values of tablets containing calcium silicate, Ditab® and/or Xylitab®, magnesium stearate, and Explotab® suggested that the amount of Explotab® was not a significant factor in determining the disintegration mechanism; however, the type of disintegrant used did alter the n value. Primojel® and Explotab®, which are in the same class of disintegrants, exhibited similar DT50, n, and k. Polyplasdone® XL exhibited a much higher n, while yielding faster DT50, suggesting that its performance is more dependent on facilitating the interfacial separation of particles. AcDiSol® showed no apparent moisture sensitivity in regards to disintegration efficiency. The use of the novel apparatus proved to be useful in measuring disintegration efficiency of rapidly disintegrating tablets and in providing valuable information on the disintegration phenomena.

Evaluation of the mechanical properties of extrusion-spheronized beads and multiparticulate systems.

BACKGROUND: The mechanical properties of extrusion-spheronized beads as part of multiparticulate systems has not been adequately studied. AIM: The purpose was to study the mechanical properties of such drug beads and blends of drug beads and glycerol monostearate (GMS)-placebo beads. METHOD: Heckel analysis (mean yield pressure, P(y)), strain rate sensitivity (SRS), elastic recovery (ER), and total work of compression (TWC) studies were conducted using a Presster(TM) linear rotary tablet machine simulator operating at several combinations of speed and force. RESULTS: The GMS-placebo beads exhibited the lowest P(y) values (9.1 +/- 1.6 MPa) and TWC (1.9 +/- 0.3 J) overall and these values steadily increased with increases in both applied speed and force. Although the placebo beads had the lowest ER values of 3.8 +/- 0.7%, these beads showed significant time-dependent deformation behavior based on their SRS value of 70.2%. Heckel analysis showed that uncoated theophylline beads containing 58% ethylcellulose were more compressible than control beads containing 58% dicalcium phosphate dihydrate, the latter having the highest overall P(y) of 79.3 +/- 3.8 MPa for the low speed/low force condition. Heckel plots also showed that 50:50 ratios of blends containing drug beads coated with either Surelease or Eudragit NE30D behaved similarly under increasing force and speed. Surelease-coated cimetidine beads gave the highest P(y), TWC, and ER values and these values were higher than Eudragit NE30D-coated beads. The 50:50 blend ratios containing coated cimetidine beads showed higher P(y), TWC, and ER values than the 60:40 ratios. CONCLUSION: Variation in the compressibility of different beads and blends can be attributed to excipients used in their formulation as well as to the drug bead-to-placebo bead ratio.

Formulation and characterization of a compacted multiparticulate system for modified release of water-soluble drugs--part 1--acetaminophen.

The aim of this study was to characterize and evaluate a modified release, multiparticulate tablet formulation consisting of placebo beads and drug-loaded beads. Acetaminophen (APAP) bead formulations containing ethylcellulose (EC) from 40-60% and placebo beads containing 30% calcium silicate and prepared using 0-20% alcohol were developed using extrusion-spheronization and studied using a central composite experimental design. Particle size and true density of beads were measured. Segregation testing was performed using the novel ASTM D6940-04 method on a 50:50 blend of uncoated APAP beads (60%EC) : calcium silicate placebo beads (10% alcohol). Tablets were prepared using an instrumented Stokes-B2 rotary tablet press and evaluated for crushing strength and dissolution rate. Compared with drug beads (60%EC), placebo beads (10% alcohol) were smaller but had higher true densities: 864.8 mum and 1.27 g/cm(3), and 787.1 mum and 1.73 g/cm(3), respectively. Segregation testing revealed that there was approximately a 20% difference in drug content (as measured by the coefficient of variation) between initial and final blend samples. Although calcium silicate-based placebo beads were shown to be ineffective cushioning agents in blends with Surelease(R)-coated APAP beads, they were found to be very compactibile when used alone and gave tablet crushing strength values between 14 and 17 kP. The EC in the APAP bead matrix minimally suppressed the drug release from uncoated beads (t(100%) = 2 h). However, while tablets containing placebo beads reformulated with glycerol monostearate (GMS) showed a slower release rate (t(60%)= 5 h) compared with calcium silicate-based placebos, some coating damage ( approximately 30%) still occurred on compression as release was faster than coated APAP beads alone. While tablets containing coated drug beads can be produced with practical crushing strengths (>8 kP) and low compression pressures (10-35 MPa), dissolution studies revealed that calcium silicate-based placebos are ineffective as cushioning agents. Blend segregation was likely observed due to the particle size and the density differences between APAP beads and calcium silicate-based placebo beads; placebo bead percolation can perhaps be minimized by increasing their size during the extrusion-spheronization process. The GMS- based placebos offer greater promise as cushioning agents for compacted, coated drug beads; however, this requires an optimized compression pressure range and drug bead : placebo bead ratio (i.e., 50:50).

Formulation and characterization of a compacted multiparticulate system for modified release of water-soluble drugs--Part II theophylline and cimetidine.

The purpose was to investigate the effectiveness of an ethylcellulose (EC) bead matrix and different film-coating polymers in delaying drug release from compacted multiparticulate systems. Formulations containing theophylline or cimetidine granulated with Eudragit RS 30D were developed and beads were produced by extrusion-spheronization. Drug beads were coated using 15% wt/wt Surelease or Eudragit NE 30D and were evaluated for true density, particle size, and sphericity. Lipid-based placebo beads and drug beads were blended together and compacted on an instrumented Stokes B2 rotary tablet press. Although placebo beads were significantly less spherical, their true density of 1.21 g/cm(3) and size of 855 mum were quite close to Surelease-coated drug beads. Curing improved the crushing strength and friability values for theophylline tablets containing Surelease-coated beads; 5.7 +/- 1.0 kP and 0.26 +/- 0.07%, respectively. Dissolution profiles showed that the EC matrix only provided 3 h of drug release. Although tablets containing Surelease-coated theophylline beads released drug fastest overall (t(44.2%) = 8 h), profiles showed that coating damage was still minimal. Size and density differences indicated a minimal segregation potential during tableting for blends containing Surelease-coated drug beads. Although modified release profiles >8 h were achievable in tablets for both drugs using either coating polymer, Surelease-coated theophylline beads released drug fastest overall. This is likely because of the increased solubility of theophylline and the intrinsic properties of the Surelease films. Furthermore, the lipid-based placebos served as effective cushioning agents by protecting coating integrity of drug beads under a number of different conditions while tableting.

Selected physical and chemical properties of Feverfew (Tanacetum parthenium) extracts important for formulated product quality and performance.

The objectives of this research are: (1) to assess selected formulation-relevant physical properties of several commercial Feverfew extracts, including flowability, hygroscopicity, compressibility and compactibility (2) to develop and validate a suitable extraction method and HPLC assay, and (3) to determine the parthenolide content of several commercial Feverfew extracts. Carr's index, minimum orifice diameter and particle-particle interaction were used to evaluate powder flowability. Hygroscopicity was evaluated by determining the equilibrium moisture content (EMC) after storage at various % relative humidities. Heckle analysis and compression pressure-radial tensile strength relationship were used to represent compression and compaction properties of feverfew extracts. An adapted analytical method was developed based on literature methods and then validated for the determination of parthenolide in feverfew. The commercial extracts tested exhibited poor to very poor flowability. The comparatively low mean yield pressure suggested that feverfew extracts deformed mainly plastically. Hygroscopicity and compactibility varied greatly with source. No commercial feverfew extracts tested contained the label claimed parthenolide. Even different batches from the same manufacturer showed significantly different parthenolide content. Therefore, extract manufactures should commit to proper quality control procedures that ensure accurate label claims, and supplement manufacturers should take into account possible differences in physico-chemical properties when using extracts from multiple suppliers.

Quality-by-design (QbD): effects of testing parameters and formulation variables on the segregation tendency of pharmaceutical powder measured by the ASTM D 6940-04 segregation tester.

The objective of this study was to examine the effects of testing parameters and formulation variables on the segregation tendency of pharmaceutical powders measured by the ASTM D 6940-04 segregation tester using design of experiments (DOE) approaches. The test blends consisted of 4% aspirin (ASP) and 96% microcrystalline cellulose (MCC) with and without magnesium stearate (MgS). The segregation tendency of a blend was determined by measuring the last/first (L/F) ratio, the ratio of aspirin concentrations between the first and last samples discharged from the tester. A 2(2) factorial design was used to determine the effects of measurement parameters [amount of material loaded (W), number of segregation cycles] with number of replicates 6. ANOVA showed that W was a critical parameter for segregation testing. The L/F value deviated further from 1 (greater segregation tendency) with increasing W. A 2(3) full factorial design was used to assess the effects of formulation variables: grade of ASP (unmilled, milled), grade of MCC, and amount of lubricant, MgS. MLR and ANOVA showed that the grade of ASP was the main effect contributing to segregation tendency. Principal Component Regression Analysis established a correlation between L/F and the physical properties of the blend related to ASP and MCC, the ASP/MCC particle size ratio (PSR) and powder cohesion. The physical properties of the blend related to density and flow were not influenced by the grade of ASP and were not related to the segregation tendency of the blend. The direct relationship between L/F and PSR was determined by univariate analysis. Segregation tendency increased as the ASP to MCC particle size increased. This study highlighted critical test parameters for segregation testing and identified critical physical properties of the blends that influence segregation tendency.

The solution and solid state stability and excipient compatibility of parthenolide in feverfew.

The objectives of this research were to evaluate the stability of parthenolide in feverfew solution state and powdered feverfew (solid state), and explore the compatibility between commonly used excipients and parthenolide in feverfew. Feverfew extract solution was diluted with different pH buffers to study the solution stability of parthenolide in feverfew. Powdered feverfew extract was stored under 40 degrees C/0% approximately 75% relative humidities (RH) or 31% RH/5~50 degrees C to study the influence of temperature and relative humidity on the stability of parthenolide in feverfew solid state. Binary mixtures of feverfew powered extract and different excipients were stored at 50 degrees C/ 75% RH for excipient compatibility evaluation. The degradation of parthenolide in feverfew solution appears to fit a typical first-order reaction. Parthenolide is comparatively stable when the environmental pH is in the range of 5 to 7, becoming unstable when pH is less than 3 or more than 7. Parthenolide degradation in feverfew in the solid state does not fit any obvious reaction model. Moisture content and temperature both play important roles affecting the degradation rate. After 6 months of storage, parthenolide in feverfew remains constant at 5 degrees C/31% RH. However, approximately 40% parthenolide in feverfew can be degraded if stored at 50 degrees C/31% RH. When the moisture changed from 0% to 75% RH, the degradation of parthenolide in feverfew increased from 18% to 32% after 6-month storage under 40 degrees C. Parthenolide in feverfew exhibits good compatibility with commonly used excipients under stressed conditions in a 3-week screening study.

The influence of granulation on super disintegrant performance.

The purpose of this study is to identify the causes of efficiency loss of super disintegrants following granulation or reworking. Two processes, precompression and prewetting, were proposed to simulate the processes during dry and wet granulation, respectively. The disintegration efficiency of the resulting disintegrant granules was tested in model formulations composed of dicalcium phosphate and lactose with the unprocessed disintegrants as controls. No significant difference was shown in the intrinsic swelling and the water uptake abilities of all super disintegrants following dry granulation. However, a significant decrease was observed for both Primojel and Polyplasdone XL10 in the rate of water being absorbed into the tablet matrix following wet granulation, but not for Ac-Di-Sol. United States Pharmacopeia (USP) disintegration testing without disc revealed a significant increase in disintegration time for tablets formulated with dry granulated Primojel and Polyplasdone XL10 and all wet granulated disintegrants. The increase in particle size following granulation appears to be the cause of the loss in disintegration efficiency. In conclusion, Ac-Di-Sol is less affected by both precompression and prewetting. The efficiency of Primojel and Polyplasdone XL10 is highly dependent on their particle size. Descreasing the particle size tends to increase their efficiency. Due to the size increase following granulation, a higher addition level of super disintegrant is required to ensure fast and uniform disintegration of tablets prepared by granulation.

The influence of swelling capacity of superdisintegrants in different pH media on the dissolution of hydrochlorothiazide from directly compressed tablets.

The purpose of this study was to investigate the efficiency of superdisintegrants in promoting tablet disintegration and drug dissolution under varied media pH. Significant reductions in the rate and extent of water uptake and swelling were observed for both sodium starch glycolate (Primojel) and croscarmellose sodium (Ac-Di-Sol) in an acidic medium (0.1 N HCl) but not for crospovidone NF (Polyplasdone XL10), a nonionic polymer. When Primojel and Ac-Di-Sol were incorporated in model formulations, a significant increase in tablet disintegration time was observed for slowly disintegrating tablets (lactose-based tablets) but not for the rapidly disintegrating tablets (dicalcium phosphate-based tablets). The dissolution rate of the model drug, hydrochlorothiazide, was found highly dependent on both tablet disintegration efficiency and the solubility of base material(s) in the testing medium. A laser diffraction particle size analyzer proved to be an effective tool for determining the intrinsic swelling of disintegrant particles in different media. Water uptake and swelling were confirmed as 2 important functions of superdisintegrants. The reduced water uptake and swelling capacity of disintegrants containing ionizable substituents in an acidic medium can potentially jeopardize their efficiency in promoting tablet disintegration and the drug dissolution rate.

Generalization of a prototype intelligent hybrid system for hard gelatin capsule formulation development.

The aim of this project was to expand a previously developed prototype expert network for use in the analysis of multiple biopharmaceutics classification system (BCS) class II drugs. The model drugs used were carbamazepine, chlorpropamide, diazepam, ibuprofen, ketoprofen, naproxen, and piroxicam. Recommended formulations were manufactured and tested for dissolution performance. A comprehensive training data set for the model drugs was developed and used to retrain the artificial neural network. The training and the system were validated based on the comparison of predicted and observed performance of the recommended formulations. The initial test of the system resulted in high error values, indicating poor prediction capabilities for drugs other than piroxicam. A new data set, containing 182 batches, was used for retraining. Ten percent of the test batches were used for cross-validation, resulting in models with R2 > or = 70%. The comparison of observed performance to the predicted performance found that the system predicted successfully. The hybrid network was generally able to predict the amount of drug dissolved within 5% for the model drugs. Through validation, the system was proven to be capable of designing formulations that met specific drug performance criteria. By including parameters to address wettability and the intrinsic dissolution characteristics of the drugs, the hybrid system was shown to be suitable for analysis of multiple BCS class II drugs.

Comparison of statistical analysis and Bayesian Networks in the evaluation of dissolution performance of BCS Class II model drugs.

This project compared the effect of formulation variables on the dissolution performance of model Biopharmaceutics Classification System (BCS) Class II drugs from hard gelatin capsules using statistical analysis and Bayesian networks. The drugs chosen for this study were carbamazepine (CAR), chlorpropamide (CHL), diazepam (DIA), ketoprofen (KET), and naproxen (NAP). Formulations contained anhydrous lactose, microcrystalline cellulose, sodium stearyl fumerate, sodium lauryl sulfate, and croscarmellose sodium. A Box-Behnken experimental design was used in the statistical analysis. The weakly acidic drugs were tested using USP apparatus II with capsule sinkers in 0.1M pH 6.8 Potassium Phosphate buffer. The weakly basic drugs were tested using USP apparatus I in 0.1N HCl buffer. Mean dissolution profiles were compared via calculation of the similarity factor. The Box-Behnken experimental design was found to be useful in assessing primary and secondary excipient effects on dissolution. The Bayesian Network developed for the dataset mirrored the key excipient effects on dissolution performance.

Functionality comparison of 3 classes of superdisintegrants in promoting aspirin tablet disintegration and dissolution.

The aims of this study are (1) to compare the disintegration efficiency, and (2) to develop a discriminating test model for the 3 classes of superdisintegrants represented by Ac-Di-Sol, Primojel, and Polyplasdone XL10. Using a digital video camera to examine the disintegration process of tablets containing the same wt/wt percentage concentration of the disintegrants, Ac-Di-Sol was found to disintegrate tablets rapidly into apparently primary particles; Primojel also apparently disintegrated tablets into primary particles but more slowly; Polyplasdone XL10 disintegrated tablets rapidly but into larger masses of aggregated particles. The differences in the size distribution generated in the disintegrated tablets likely contribute to the drug dissolution rate differences found for aspirin tablets with similar disintegration rates. The aspirin tablet matrix is proposed as a model formulation for disintegrant efficiency comparison and performance consistency testing for quality control purposes.

Influence of methacrylic and acrylic acid polymers on the release performance of weakly basic drugs from sustained release hydrophilic matrices.

Weakly basic drugs and their salts exhibit a drop in aqueous solubility at high pH conditions, which can result in low and incomplete release of these drugs from sustained release formulations. The objective of this study is to modulate matrix microenvironmental pH by incorporation of acidic polymers and thus enhance the local solubility and release of basic drugs in high pH environment. Two weakly basic drugs, papaverine hydrochloride and verapamil hydrochloride with widely different pKa and aqueous solubilities at the pH of interest (6.8), were investigated for their release from hydrophilic matrices and the effect of a methacrylic (Eudragit L100-55) and an acrylic acid polymer (Carbopol 71G), were studied. For papaverine HCl, release increased with an increase in the levels of the acidic polymer used. Direct measurement of matrix pH using microelectrodes illustrated that the mechanism of release enhancement was based on modulation of microenvironmental pH. For verapamil HCl, incorporation of L100-55 resulted in release retardation due to an interaction between the anionic polymer and the cationic drug and the extent of retardation increased with an increase in the polymer level. The interaction product was characterized by NIR, FT-IR, and MTDSC techniques. Verapamil HCl release from Carbopol 71G based matrix tablets was higher than that from conventional hydroxypropyl methylcellulose (HPMC) based matrices, without any incorporated acidic additives.

A study of the effects of curing and storage conditions on controlled release diphenhydramine HCl pellets coated with Eudragit NE30D.

The objective of this study was to investigate the possible impacts of curing and storage conditions on dissolution of controlled release diphenhydramine HCl pellets coated with EUDRAGIT NE30D. The accumulative percentage of dissolved active drug was used as the response in three statistical experimental design studies: 32 full factorial, Box-Behnken and 2(3) designs. By only considering curing temperature and curing time, both factors were found to significantly affect the dissolution rate, but curing temperature had greater impact than curing time. When considering polymer coating level, curing temperature and curing time together, polymer coating level and curing temperature had important effects on dissolution rate, but curing time became insignificant among these three factors. The addition of the water-soluble additives hydroxypropyl methyl cellulose and mannitol made coating films less sensitive to curing, and there was little or no difference in their effect in the model studied. Lower levels of a water-insoluble additive (kaolin) had little impact on dissolution; however, when the level of water-insoluble additive increased, the coating film became more sensitive to curing, especially at the lower curing temperature of 30 degrees C.

Potential application of silicified microcrystalline cellulose in direct-fill formulations for automatic capsule-filling machines.

Silicified microcrystalline cellulose (SMCC) has physico-mechanical properties that may be of advantage in hard gelatin capsule formulations. The present research was designed to evaluate and compare SMCC's performance to that of other excipients commonly used in hard gelatin capsule direct-fill formulations. All capsules were filled using a fully instrumented Zanasi LZ-64 automatic capsule-filling machine. Four grades of SMCC [SMCC 50, SMCC 90, SMCC HD90, and an experimental-grade (SMCC X)] were investigated. Anhydrous lactose (direct tableting grade), pregelatinized starch (PGS) (Starch 1500), and microcrystalline cellulose (MCC) (Emcocel 90M) were chosen as the control fillers. The following properties were measured: capsule fill weight, relative standard deviation of capsule fill weight, plug ejection force, plug maximum breaking force (MBF), and the dissolution of two marker compounds (acetaminophen and piroxicam). The MBF of capsule plugs increased with increases in compression force from 50N to 100N for all excipients. Starch 1500 and anhydrous lactose plugs exhibited the lowest MBF values. PGS, anhydrous lactose, SMCC HD90, and SMCC X consistently exhibited the lowest ejection forces under the same experimental conditions, this difference being most apparent at higher compression forces. Different patterns were observed in the way compression force affected the fill weight of the materials studied. Overall, there was no clear pattern to the way the relative standard deviation (RSD) of capsule fill weight varied with encapsulation conditions. Sodium stearyl fumarate (SSF) appeared to be somewhat more efficient at reducing the ejection force than magnesium stearate at the same level, this difference being especially apparent at the 14-mm piston height. Formulations containing either 5% piroxicam, 30% acetaminophen, or 50% acetaminophen exhibited faster drug dissolution when MCC or SMCC was the filler than when anhydrous lactose or PGS was the filler. The presence of colloidal silicon dioxide in SMCC did not appear to influence the dissolution of these drugs. The data suggest that SMCC could be a suitable direct-fill excipient for hard shell capsule formulations.

Comparison of the formulation requirements of dosator and dosing disc automatic capsule filling machines.

The overall objective of this study was to provide 'semi-quantitative' or 'rigorous' definitions of the fluidity, lubricity and compactibility requirements of formulation for representative dosator and dosing disc capsule filling machines. To that end, model formulations were developed for those properties using Carr's compressibility index, ejection force, and plug breaking force at a specified compression force to gauge fluidity, lubricity, and compactibility, respectively. These formulations were each encapsulated on an Hofliger-Karg GKF-400 dosing disc machine and a Zanasi LZ-64 dosator machine. Each machine was instrumented to measure plug compression and ejection forces. The encapsulation process was evaluated for %CV of fill-weight, ejection force, plug breaking force and the dissolution of marker drugs incorporated in the formulations. The f2 metric was used to compare dissolution profiles. The results suggest: (1) formulations should meet different flow criteria for successful encapsulation on the two machines, (2) a relatively lower level of lubricant may be sufficient for the dosing disc machine, (3) a higher degree of formulation compactibility is needed for the dosator machine, and (4) transferring formulations between these machine types (same class, different subclass per FDA's SUPAC-IR/MR Manufacturing Equipment Addendum) could be challenging. In certain cases dissolution profiles for the same formulation filled on the two machines with equivalent compression force were different based on f2 < 50. Overall, the results of this study suggest a range of formulation characteristics appropriate for transferring formulations between these two types of machines.

Excipient compatibility study of Hypericum perforatum extract (St. John's wort) using similarity metrics to track phytochemical profile changes.

The formulation of botanical dietary supplements is challenging due to their complex activity-composition relationship, as well as physical and chemical stability issues. As excipient compatibility testing is a major component of sound formulation development, the objectives of this work were: (1) explore excipient compatibility storage paradigms; (2) determine interactions between phytochemicals of interest in Saint John's Wort (SJW) with several excipients; and (3) explore the application of similarity metrics to the data. Modifications to conventional isothermal stress testing paradigms included additional storage conditions of heat and moisture (5, 50 degrees C, 5 and 0% added water), as well as more rigorous controls. Binary blends of SJW and ten commonly used excipients were prepared and neat SJW was used as control. After 3 weeks, the percentage remaining of each phytochemical was determined by HPLC. Several similarity metrics were applied to the data. Common storage paradigms were suitable for excipient compatibility testing when controls of neat material are stored under similar conditions and the percentage of phytochemicals remaining in excipient:SJW blends and neat SJW are compared. Excipient incompatibilities were determined for SJW phytochemicals of interest. Similarity metrics applied to the phytochemical profiles conveniently summarized the data. This work allows logical decisions to be made regarding the formulation of SJW.

Evaluation of the plug formation process of silicified microcrystalline cellulose.

To investigate the powder plug formation process of silicified microcrystalline cellulose (SMCC) under compression forces consistent with automatic capsule-filling machines, a single-ended saw-tooth wave was used to make powder plugs with different heights (6, 8, 12 mm), at two different punch speeds (1 and 50 mm/s) on a tablet compaction simulator. SMCC was compared to Starch 1500, anhydrous lactose (direct tableting grade), and microcrystalline cellulose. Heckel analysis showed that 'apparent mean yield pressures' (AMYP) of all tested materials increased with an increase in the plug height and punch speed. AMYP appeared to depend on the material type and punch speed. Not all materials fit the Shaxby-Evans relationship at such low compression forces (less than 250 N). Only SMCC 90, SMCC HD90 and anhydrous lactose data fit the equation at both punch speeds. Due to poor axial load transmission, the R values of all tested materials decreased with an increase in the plug height. The experimental data fit the Kawakita equation quite well. Overall, Kawakita's b values were inversely related to AMYP values. The maximum breaking force (MBF) of a 12 mm plug formed at a punch speed of 50 mm/s correlated well with the work of compaction, except for SMCC HD90 and SMCC X, which exhibited very high MBF values. This research demonstrated that several grades of SMCC produced plugs having higher MBF than anhydrous lactose and Starch 1500 under similar compression conditions. The apparently higher compactability of these materials at low plug formation forces may be beneficial in developing direct fill formulations for automatic capsule filling machines.