Larry L. Augsburger

Selected physical and chemical properties of commercial Hypericum perforatum extracts relevant for formulated product quality and performance.

Objective. The complex composition-activity relationship of botanicals such as St Johns Wort (SJW) presents a major challenge to product development, manufacture, and establishment of appropriate quality and performance standards for the formulated products. As part of a larger study aimed at addressing that challenge, the goals of the present study are to (1) determine and compare the phytochemical profiles of 3 commercial SJW extracts; (2) assess the possible impact of humidity, temperature, and light on their stability; and (3) evaluate several physical properties important to the development of solid dosage forms for these extracts. Methods. An adapted analytical method was developed and validated to determine phytochemical profiles and assess their stability. The extract physical properties measured were particle size (Malvern Mastersizer), flow (Carrs compressibility index; minimum orifice diameter), hygroscopicity (method of Callahan et al), and low-pressure compression physics (method of Heda et al). Results. The phytochemical properties differed greatly among the extracts and were extremely sensitive to changes in storage conditions, with marked instability under conditions of elevated humidity. All extracts exhibited moderate to free-flow properties and were very hygroscopic. Compression properties varied among the extracts and differed from a common use excipient, microcrystalline cellulose. Conclusions. Three commercial sources of SJW extracts exhibited different physical and chemical properties. Standardization to 1 or 2 marker compounds does not ensure chemical equivalence nor necessarily equivalent pharmacological activity. Flow and compression properties appear suitable for automatic capsule-filling machines, but hydroscopicity and the moisture sensitivity of the phytochemical profile are concerns.

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.

Multiple Sources of Sodium Starch Glycolate, NF: Evaluation of Functional Equivalence and Development of Standard Performance Tests

Sodium starch glycolate is a commonly used super-disintegrant employed to promote rapid disintegration and dissolution of IR solid dosage forms. It is manufactured by chemical modification of starch, i.e., carboxymethylation to enhance hydrophilicity and cross-linking to reduce solubility. It has been reported in the literature that the source of starch, particle size, amount of sodium chloride (reaction by-product), viscosity, degree of substitution and cross-linking affect the functionality of sodium starch glycolate. Compendial assays provide an accurate representation of the chemical quality of an excipient, but they are not useful in describing the physical properties associated with the excipients. Physical characterization of sodium starch glycolate, NF revealed differences in particle size, surface area, porosity, surface morphology, and viscosity between two of the three sources examined. An automated liquid uptake test (in neutral and acidic medium) demonstrated similar initial rates of uptake, however, the extent of liquid uptake differed for the disintegrant powders examined. Settling volume was also observed to be different for the disintegrant from two sources. Lowering the pH of the medium reduced the rate and extent of liquid uptake and the settling volume in all instances. The extent of liquid uptake and settling volume was observed to be higher for the smaller sieve fractions in either medium. Although differences were also observed in the axial and radial disintegration force measurements of the pure disintegrant compacts, disintegration and dissolution of a model drug (hydrochlorothiazide) from either the soluble or insoluble core did not reveal any significant differences between the multiple sources.

The Influence of Product Brand-to-Brand Variability on Superdisintegrant Performance A Case Study with Croscarmellose Sodium

The purpose of this study is to investigate factors influencing croscarmellose sodium functionality with special emphasis on developing a discriminating model tablet formulation to evaluate product brand-to-brand variability. The particle size distribution, water uptake, and swelling properties of five brands of croscarmellose sodium in either neutral water or 0.1 N HCl were studied. Differences were observed in all properties between brands. Media with acidic pH had a negative impact, but to different extents, on both the water uptake and swelling of all croscarmellose sodium brands due to the presence of carboxymethyl sodium substituents. A tablet matrix composed of lactose (75% w/w) and dicalcium phosphate (25% wt/wt) was used to compare the functional equivalency of the five brands of croscarmellose sodium. The tablet disintegration times were inversely proportional to the swelling ability of superdisintegrant in the testing medium regardless of medium temperature and disintegrant concentration. In conclusion, the particle size, total degree of substitution, and the ratio of basic to acidic substituents are important factors that should be considered during product optimization. The tablet matrix composed of lactose and dicalcium phosphate at a weight ratio of 3:1 can be used as a model formulation for product lot-to-lot consistency and product brand-to-brand comparison purposes.

Increasing the Dissolution Rate of a Low-Solubility Drug Through a Crystalline-Amorphous Transition: A Case Study with Indomethicin

The purpose of this research is to further the understanding of the crystalline to amorphous phase transition (amorphization) that occurs when some crystalline drugs are dry blended with porous adsorbents. Indomethacin (IMC) and three grades of silica gel (SGs) were used in the study. Amorphization of crystalline IMC occurs rapidly during dry mixing with SG and was independent of mixing intensity and time. Extent of amorphization increases with lower ratios of IMC:SG and with decreased IMC and SG particle size. Blocking H-bonding silanol groups on SG by chemical modification reduced the extent of amorphization. IMC-SG mixtures showed improved dissolution rates over crystalline IMC, the improvement being directly related to the extent of amorphization. To preserve the improved dissolution rate, mixtures should be protected from moisture and heat. This approach holds promise as a mean of improving the dissolution rate of sparingly soluble drugs such as IMC.

Quantitative measurement of indomethacin crystallinity in indomethacin-silica gel binary system using differential scanning calorimetry and X-ray powder diffractometry

Differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRPD) methods were developed for the quantitative analysis of the crystallinity of indomethacin (IMC) in IMC and silica gel (SG) binary system. The DSC calibration curve exhibited better linearity than that of XRPD. No phase transformation occurred in the IMC-SG mixtures during DSC measurement. The major sources of error in DSC measurements were inhomogeneous mixing and sampling. Analyzing the amount of IMC in the mixtures using high-performance liquid chromatography (HPLC) could reduce the sampling error. DSC demonstrated greater sensitivity and had less variation in measurement than XRPD in quantifying crystalline IMC in the IMC-SG binary system.

Study of crystallization of endogenous surfactant in Eudragit NE30D-Free films and its influence on drug-release properties of controlled-release diphenhydramine HCI pellets coated with Eudragit NE30D

This study investigates the crystallization of the endogenous surfactant nonoxynol 100 in Eudragit NE30D-free films during storage and the influences of nonoxynol 100 on the dissolution of diphenhydramine hydrochloric acid (HCL) pellets coated with Eudragit NE30D before and after aging at ambient conditions. Polarizing light microscopy showed that when Eudragit NE30D-free films were stored at ambient conditions, off-white, flower-shaped crystals formed and increased in the polymer film as storage time increased. Also, x-ray diffraction showed polymer crystals in the aged free film. Thermogravimetric analysis showed no evidence of combined volatile molecules with the polymer molecules, and Fourier transformed infrared spectroscopy (FTIR) data suggested the same chemical composition of the polymer before and after phase separation. Further, from normal light microscopy, the appearance of the melting droplets in the polymer film indicated that the polymer molecules did not form the crystals. After the extraction of nonoxynol 100 by water, the free film formed by the water-extracted Eudragit NE30D was found free of the crystals after aging at the same conditions. The combination of the thermogravimetric analysis, FTIR, and microscopy showed that the origin of the crystals in dry Eudragit NE30D-free films came from nonoxynol 100, and not from the polymer molecules themselves. Monitoring by differential scanning calorimeter, it was found that the rates of crystallization of nonoxynol 100 were faster when the films were stored at 30°C and 40°C than when stored at ambient conditions and 45°C. When stored at −5°C, the crystallization rate was nearly zero. As the temperature got closer to melting temperature, the crystallization rate was very low because the system was in a thermodynamically disfavored state. The rate gradually increased and finally passed through a maximum as the crystallization temperature decreased. As the temperature kept decreasing, the crystallization rate became small again and eventually stopped because the system turned into a kinetically disfavored state. Because the phase transition of nonoxynol 100 in Eudragit NE30D occurred at ambient conditions, its influence on the dissolution of diphenhydramine HCL pellets coated with Eudragit NE30D was studied. Three different levels of nonoxynol 100 were used in Eudragit NE30D dispersions to make 3 different batches of Eudragit NE30D film-coated, controlled-release diphenhydramine HCL pellets. The results showed the dissolution rate increased as the level of nonoxynol 100 increased in the coating formula. Compared to the commonly used water-soluble additive human peripheral mononuclear cell, nonoxynol 100 was more effective in enhancing the dissolution of diphenhydramine HCL from pellets coated with Eudragit NE30D. Further study showed that the phase separation of the surfactant during aging tends to stabilize or slightly increase dissolution rates at higher surfactant levels.

Estimation of capping incidence by indentation fracture tests

The purpose of this study was to predict the capping tendencies of pharmaceutical powders by creating indentation fracture on compacts. Three sets of binary mixtures containing different concentrations of each ingredient were used in the study. The binary mixtures were chosen to represent plastic-plastic, plastic-brittle, and brittle-brittle combination of materials. The mixtures were tableted at different pressures and speeds on Prester®, a tablet press simulator. These mixtures were also compacted on the Instron® Universal Testing Machine 4502. Static indentation tests were done on these compacts at different depths until surface cracking and chipping were observed. The extent of surface cracking and chipping was observed from light microscope and scanning electron microscope images. A rank order correlation was observed between lamination susceptibility and the depth at which indentation failure occurred. It was concluded that indentation fracture tests could provide a useful estimate of lamination properties of pharmaceutical powders.

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 Johns 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.

Scale-up effects on dissolution and bioavailability of propranolol hydrochloride and metoprolol tartrate tablet formulations

1bstractThis study evaluated the effects of batch size on the in vitro dissolution and the in vivo bioavailability of immediate release formulations of propranolol hydrochloride and metoprolol tartrate. The formulations were manufactured as small and large batches (6 kg and 60 kg for propranolol; 14 kg and 66 kg for metoprolol), and dissolution was performed using USP Apparatus I at 100 rpm and pH 1.2. Two panels of 14 subjects each were randomly assigned to receive the small and large batches of either propranolol or metoprolol in an open randomized single-dose study. Blood samples were collected over a 24-hour (propranolol) or 18-hour (metoprolol) period and analyzed by validated methods. As determined by thef2 metric (similarity factor), the dissolution of the small and large batches of propranolol and metoprolol was similar. The mean Cmax and AUCinf for the small batch of propranolol were 79.0 μ g/L and 536 μ g/L/hr and for the large batch they were 83.5 μ g/L and 575 μ g/L/hr. Cmax and AUCinf for the small batch of metoprolol were found to be 95.5 μ g/L and 507 μ g/L/hr and for the large batch, 95.1 μ g/L and 495 μ g/L/hr. The 90% confidence intervals for the small and large batches were within the 80% to 120% range for InCmax, and InAUCinf for both the propranolol and metoprolol formulations. These results suggest that the scale-up process does not significantly affect the bioavailability of highly soluble, highly permeable drugs and in vitro dissolution tests may be useful in predicting in vivo behavior.