Stephen W. Hoag

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.

Quality by Design I: Application of Failure Mode Effect Analysis (FMEA) and Plackett–Burman Design of Experiments in the Identification of “Main Factors” in the Formulation and Process Design Space for Roller-Compacted Ciprofloxacin Hydrochloride Immediate-Release Tablets

As outlined in the ICH Q8(R2) guidance, identifying the critical quality attributes (CQA) is a crucial part of dosage form development; however, the number of possible formulation and processing factors that could influence the manufacturing of a pharmaceutical dosage form is enormous obviating formal study of all possible parameters and their interactions. Thus, the objective of this study is to examine how quality risk management can be used to prioritize the number of experiments needed to identify the CQA, while still maintaining an acceptable product risk profile. To conduct the study, immediate-release ciprofloxacin tablets manufactured via roller compaction were used as a prototype system. Granules were manufactured using an Alexanderwerk WP120 roller compactor and tablets were compressed on a Stokes B2 tablet press. In the early stages of development, prior knowledge was systematically incorporated into the risk assessment using failure mode and effect analysis (FMEA). The factors identified using FMEA were then followed by a quantitative assessed using a Plackett–Burman screening design. Results show that by using prior experience, literature data, and preformulation data the number of experiments could be reduced to an acceptable level, and the use of FMEA and screening designs such as the Plackett Burman can rationally guide the process of reducing the number experiments to a manageable level.

Assessment of NIR Spectroscopy for Nondestructive Analysis of Physical and Chemical Attributes of Sulfamethazine Bolus Dosage Forms

The goal of this study was to assess the utility of near infrared (NIR) spectroscopy for the determination of content uniformity, tablet crushing strength (tablet hardness), and dissolution rate in sulfamethazine veterinary bolus dosage forms. A formulation containing sulfamethazine, corn starch, and magnesium stearate was employed. The formulations were wet granulated with a 10% (wt/vol) starch paste in a high shear granulator and dried at 60°C in a convection tray dryer. The tablets were compressed on a Stokes B2 rotary tablet press running at 30 rpm. Each sample was scanned in reflectance mode in the wavelengths of the NIR region. Principal component analysis (PCA) of the NIR tablet spectra and the neat raw materials indicated that the scores of the first 2 principal components were highly correlated with the chemical and physical attributes. Based on the PCA model, the significant wavelengths for sulfamethazine are 1514, (1660–1694), 2000, 2050, 2150, 2175, 2225, and 2275 nm; for corn starch are 1974, 2100, and 2325 nm; and for magnesium stearate are 2325 and 2375 nm. In addition, the loadings show large negative peaks around the water band regions (≈1420 and 1940 nm), indicating that the partial least squares (PLS) models could be affected by product water content. A simple linear regression model was able to predict content uniformity with a correlation coefficient of 0.986 at 1656 nm; the use of a PLS regression model, with 3 factors, had anr2 of 0.9496 and a sandard error of calibration of 0.0316. The PLS validation set had anr2 of 0.9662 and a standard error of 0.0354. PLS calibration models, based on tablet absorbance data, could successfully predict tablet crushing strength and dissolution in spite of varying active pharmaceutical ingredient (API) levels. Prediction plots based on these PLS models yielded correlation coefficients of 0.84 and 0.92 on independent validation sets for crushing strength and Q120 (percentage dissolved in 120 minutes), respectively.

Plasticizer effects on physical-mechanical properties of solvent cast Soluplus® films.

Soluplus® is a novel amphiphilic polymer that has been shown to enhance the solubility and drug dissolution rate of poorly soluble drugs. However, there still is a lack of information regarding the physical mechanical properties of Soluplus® with addition of the plasticizers. This study characterized the mechanical properties of Soluplus® with four different plasticizers. The plasticizers selected were polyethylene glycol 6, triethyl citrate, propylene glycol, and glycerin; they were studied at three different levels (15%, 20%, and 25% w/w). The effects of these plasticizers on the glass transition temperature, tensile strength, percent elongation, and Young’s modulus of free films made from Soluplus® were measured and the toughness and ratio of tensile strength to Young’s modulus were calculated. These results showed these four plasticizers are capable to plasticizing Soluplus® as indicated by the glass transition temperature lowering, tensile strength, and Young’s modulus while increasing the percent elongation and film toughness. Among the plasticizers tested, polyethylene glycol 6 showed greatest changed in the mechanical properties studied.

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 μm and 1.27 g/cm3, and 787.1 μm and 1.73 g/cm3, 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®-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 (t100% = 2 h). However, while tablets containing placebo beads reformulated with glycerol monostearate (GMS) showed a slower release rate (t60%= 5 h) compared with calcium silicate-based placebos, some coating damage (∼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).

Analysis of curing of a sustained release coating formulation by application of NIR spectroscopy to monitor changes physical-mechanical properties.

The focus of the study was to explore the physical-mechanical properties of curing films and use these properties as a reference for models that relate NIR spectra to the extent of curing. Cast films were cured at 40, 50, and 60°C from 1 to 48 h before being scanned on an NIR Spectrometer and analyzed for physical-mechanical properties using an Instron(®) material testing system. The studies show clear dependence of the physical-mechanical properties on the time and temperature used for curing. Principal component analysis (PCA) and parallel factor analysis (PARAFAC) were performed to investigate the effect of curing on the films. Both PCA and PARAFAC analysis of the NIR spectra showed that spectral features could be directly related to the changes associated with the triethyl citrate (TEC), which directly affected the physical-mechanical properties during curing. Partial least squares (PLS) models were developed that related NIR spectra to the physical-mechanical properties. The use of the Youngs Modulus as a reference for NIRS model development resulted in good prediction and was determined to be the best reference for model development. This study demonstrated the NIRS could predict the Youngs Modulus which may be used to indicate the extent of curing.

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/cm3 and size of 855 μm 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 (t44.2% = 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.

Quality of antiretroviral and opportunistic infection medications dispensed from developing countries and Internet pharmacies.

Generic manufacturers help decrease the cost of antiretroviral (ARV) and antimicrobial medications which are used to treat opportunistic infections (OIs) in developing countries. Concerns have been expressed about potential quality issues with such medications as a result of the identification of numerous counterfeit medications in developing countries. However, few studies have assessed the quality of these medications using the United States Pharmacopeia (USP) compendial standards. The goal of this study was to assess the quality of ARV and OI medications obtained from various sources, including South Africa, United States, China, Ethiopia, Thailand, Laos, Mexico, Nigeria and five Internet pharmacies.

Intranasal scopolamine affects the semicircular canals centrally and peripherally

Space motion sickness (SMS), a condition caused by an intravestibular conflict, remains an important obstacle that astronauts encounter during the first days in space. Promethazine is currently the standard treatment of SMS, but scopolamine is used by some astronauts to prevent SMS. However, the oral and transdermal routes of administration of scopolamine are known to have substantial drawbacks. Intranasal administration of scopolamine ensures a fast absorption and rapid onset of therapeutic effect, which might prove to be suitable for use during spaceflights. The aim of this study was to evaluate the effects of intranasally administered scopolamine (0.4 mg) on the semicircular canals (SCCs) and the otoliths. This double-blind, placebo-controlled study was performed on 19 healthy male subjects. The function of the horizontal SCC and the vestibulo-ocular reflex, as well as the saccular function and utricular function, were evaluated. Scopolamine turned out to affect mainly the SCCs centrally and peripherally but also the utricles to a lesser extent. Centrally, the most probable site of action is the medial vestibular nucleus, where the highest density of muscarinic receptors has been demonstrated and afferent fibers from the SCCs and utricles synapse. Furthermore, our results suggest the presence of muscarinic receptors in the peripheral vestibular system on which scopolamine has a suppressive effect. Given the depressant actions on the SCCs, it is suggested that the pharmacodynamic effect of scopolamine may be attributed to the obliteration of intravestibular conflict that arises during (S)MS.

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

Abstract 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% β-AL), DCL11 (spray dried α-lactose monohydrate containing ∼15% amorphous lactose) and DCL15 (granulated α-lactose monohydrate containing ∼12% β-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).