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This review includes the viewpoints of three pharmaceutical scientists tracing the origins of the generic drug industry, examining the recent generic drug controversies, and offering suggestions to hospital practitioners for coping with the controversies.

A description is presented of an Instron physical testing instrument which was adapted to permit its utilization in the evaluation of the compressing characteristics of drug particles and granules. Measurements were performed on a bed of a readily and a poorly compressible solid, as well as granules of these solids made with several commonly used pharmaceutical binding agents. It was found that potassium chloride crystals and granules deformed at lower compression loads than those of potassium citrate. The influence of crystal and granule size and granulating agents on these measurements was found to be relatively small when compared with the inherent properties of each salt. The relationship between the logarithm of the load and the deformation showed a change of slope depending on load range. An attempt was made to obtain a parameter of compressibility having practical implications and leading to a better theoretical understanding of the mechanism of bonding of solids under pressure.

A method for estimation of antioxidant efficiency in pharmaceutical oils is described. The procedure depends upon the measurement of malonaldehyde which is produced during the oxidative degradation of the oils. The malonaldehyde is condensed with 2-thiobarbituric acid (TBA) to obtain a pink chromogen which is measured spectrophotometrically at 530 mμ. The influence of 0.02 per cent butylated hydroxyanisole, butylated hydroxytoluene, nordihydroguaiaretic acid, propyl gallate, lauryl gallate, gentisic acid, ascorbyl palmitate, and acetone sodium bisulfite upon the formation of malonaldehyde in peanut, sesame, corn, cottonseed, and soya oils is reported.

The protective influence of glass of various spectral transmission characteristics on the light-induced fading of colored tablets has been investigated. The glasses were evaluated as to their effect on the fading rate of tablets colored with FD&C Blue No. 1 and D&C Yellow No. 10. The glass samples evaluated included flint, Georgia green, emerald green, champagne green, and ultraviolet-absorbing green, as well as plastic coated lantern slides incorporating ultraviolet-absorbing agents. The apparent rates of fading of the dyes were determined following exposure of the tablets to exaggerated illumination. Reflectance measurements performed on the tablets at intervals indicated that amber glass apparently afforded the greatest protection against the fading of both dyes under the condition of study.

Assay results for a single sample stored in an elevated temperature oven for a known period of time may be in error if instantaneous heating and cooling of the sample is not achieved. For usual kinetic studies however, the storage behavior of a group of samples which have been placed in the oven at the same time is followed. Theoretical and experimental considerations are presented to show that in the case of apparent first-order reactions the assay values for all samples in the group are subjected to the same degree of error. Rates of degradation calculated from the assay data are identical to those measured under isothermal conditions. Consequently, decomposition rates obtained under the usual oven storage conditions, where time lags in heating and cooling samples exist, give useful information for estimating product stability.

The photostabilizing effect of the ultraviolet absorber 2,4-dihydroxybenzophenone for tablets colored with three certified dyes was evaluated. Two sources of light were employed; one approximating the spectral energy distribution of sunlight and the other simulating ordinary room illumination. The apparent rates of fading for FD&C Yellow No. 5, FD&C Blue No. 1, and FD&C Red No. 3 were determined under each light source. The relationship existing between the protective properties of the ultraviolet absorber, the absorption characteristics of the dyes, and the spectral energy distribution of the artificial light sources is discussed.

A description of a comprehensive record and control system employed as an integral part of the stability laboratory is presented. This is intended to facilitate the recording of the numerous data that become available from the products undergoing stability testing and to provide an accurate system for sending of samples for analysis at the correct time intervals. Stability evaluation cards used to record data of a product undergoing stability testing are described. Different color cards are employed for different storage conditions. The information preprinted on the cards varies according to the type of dosage form. The labels to be placed on the products being stored are shown to be similar in color to that of the stability evaluation cards. The captions preprinted on them are discussed. A simple foolproof control method for sampling preparations at designated time intervals is demonstrated. Simplified analysis report forms to be employed when samples are sent to the other groups for testing are illustrated and discussed. In order to have available a graphic icture of the progress for the various dosage forms being tested, the use of a visual low chart is described.

A new approach to possible preservation of drugs undergoing hydrolytic degradation is presented. It is shown that the rate of hydrolysis of benzocaine in aqueous solution can be substantially inhibited by addition of caffeine which has previously been shown to complex with this drug. Presence of two and one‐half per cent of caffeine in the system resulted in reduction of the hydrolytic rate to less than one‐fifth of that in absence of the xanthine. Mathematical analysis of the results obtained indicates that the complexed form of the drug does not undergo, surprisingly, any perceptible cleavage at the ester linkage.

The design and operating principles of an apparatus capable of measuring the inherent static charge on materials, as well as being able to induce a positive or negative electrostatic potential, are described. The dual polarity high voltage power supply unit of this instrument can apply up to 10,000 v. to the materials under study. The voltage accumulation or decay of the sample being evaluated in the modified Faraday cage of the apparatus can be read on the ammeter of the electrostatic voltage sensing pistol or displayed on an X-Y recorder from the sensing pistol. Measurements are reported on the relative static electrification tendencies of sodium chloride, stearic acid, sulfisomidine, and iodochlorhydroxyquin when exposed to negative and positive potentials of 6,000 v.

Pharmaceutical products such as jellies packaged in collapsible tubes cannot be properly sterilized in conventional steam autoclaves because of expansion or bursting of the tubes. Similarly, leakage at the cap occurs during the sterilization of screw-capped bottles. In this report, a redesigned steam autoclave is described which permits the practical sterilization of these pharmaceutical formulations. This autoclave is a dual-control unit permitting the introduction of air under pressure into the chamber so as to obtain a total air plus steam pressure greater than that of the vapor pressure within the containers. In addition, this unit allows for a reduction in chamber temperature without loss of chamber pressure during the cooling cycle. The suitability of this dual-control autoclave for the sterilization of the aforementioned products under various conditions of temperature and pressure was determined. Data are presented indicating that these pharmaceutical products can be effectively sterilized without deleterious effects to the containers. The jellies and solutions used in this investigation were heavily contaminated with B. cereus spores. Recordings of the temperature within the containers and chamber show that there is a lag in the rise and fall of the temperature within the containers as compared to that of the chamber.

The protective action of epoxy lining on rubber stoppers of natural, neoprene, and butyl rubber was evaluated against unlined stoppers of the same composition for sorption of preservative from vial solutions and extractives leached from closures into the solution. For the preservatives tested—namely, p -chloro- β -phenylethyl alcohol and its nonchlorinated analog, phenylethyl alcohol—no protective action against sorption was exhibited by the lined closures. The solutions used in the extractives study were water, 10 per cent ethanol, 50 per cent polyethylene glycol 300, 50 per cent N , N -dimethylacetamide, and 2 per cent benzyl alcohol. The lining on the closures was found to afford protection against leaching. For both the sorption and extractives studies, the butyl rubber closures exhibited optimal stability.

A description of the complexities involved in trouble shooting of pharmaceutical products is presented. Also discussed are several organizational structures that can serve as effective cover for trouble shooting personnel. Several examples of trouble shooting situations are used to illustrate the importance of cooperative interdepartmental interactions.

Electrocapillary curves at a series of concentrations of the diastereoisomeric ephedrines in 1 N NaOH and of the corresponding salts in 1 N HCl have been determined. The electrocapillary maximum (e.c.m.) was shifted to more positive potentials with an increase in concentration in each instance. Adsorption of the free bases on mercury was greater than that of the cations. The fractional surface coverage of the electrode by the cations was found to be highly dependent upon potential, with maximum coverage occurring at potentials slightly more negative than the e.c.m. Coverage by the free bases was largely independent of potential over a wide range of potentials. The Gibbs surface excess of the isomeric ephedrinium ions was the same from 0.001 M to 0.2 M . At low coverage for a given reduced concentration, the surface excess of (−)-ephedrine was greater than that of (+)-ψ-ephedrine; whereas at high coverage, the surface excess of the diastereoisomers was the same. These results imply that at high surface coverage, orientation of both isomers at the electrode is the same with planar adsorption of the aromatic nucleus on the electrode surface and the side chain in solution; at low surface coverage, the molecules lie flat on the electrode surface. The extra electrostatic work for bringing (+)-ψ-ephedrine to the surface, compared with (−)-ephedrine, was interpreted in terms of the conformations of the diastereoisomers in the bulk of the solution and at the surface. Polarograms exhibited no discrete catalytic hydrogen wave; however, the limiting currents at potentials preceding discharge appeared to be catalytic currents. The catalytic current of (−)-ephedrine was greater than that of (+)-ψ-ephedrine in borate buffers. A linear dependence of catalytic current on the concentration of each isomer was observed over a narrow concentration range.

The influence of excipients and lubricants on the chemical and physical stability of tablets is demonstrated. Tablet color stability and its measurement is reviewed. The applicability of chemical kinetic principles and the Arrhenius relationship to stability data for tablet systems is illustrated. The importance of the package to product stability is shown. The utility of exaggerated temperature, light, and humidity conditions in the stability testing of tablet dosage forms is demonstrated. The importance and significance of a well-organized stability testing program for evaluating the physical and chemical stability of solid dosage forms are discussed.

In this study, a specially designed low-conductance bridge was employed for the determination of eutectic temperatures by electrical resistivity. This method has been found to be more reliable than the usually employed temperature-time measurements. The bridge consists of four wide-range decades and eight narrowrange decades from 0-10 12 ohms. An X-Y recorder was used for plotting the conductance as a function of temperature. A specially fabricated chamber, designed to function at controlled pressures, was employed for the eutectic measurements. Eutectic temperatures for a series of organic salts have been found to be considerably higher than values previously believed. The eutectics for these particular compounds varied from −0.75° to −12°. A mathematical expression has been developed, illustrating the relationship between the eutectic temperature and the solubility parameter. Calculated values agree favorably with the experimental values for a series of organic salts. Mannitol and lactose have little or no effect on the solubility or eutectic temperature of the various agents studied. Utilization of data such as these has been found to be extremely valuable in the design of lyophilization cycles.

The relative light fastness of several certified water-soluble dyes and their corresponding lakes were investigated. The water-soluble dyes studied were FD&C Red No. 1, FD&C Blue No. 1, and FD&C Yellow No. 5. The lakes investigated consisted of water-soluble dyes precipitated on a suitable substrate and were D&C Red No. 1 lake, D&C Blue No. 1 lake, and D&C Yellow No. 5 lake. Tablets containing the above colorants were stored under normal and exaggerated illumination of similar spectral energy distribution. The apparent rates of fading of the several dyes were evaluated. The differences in light fastness between lakes and water-soluble dyes are discussed.

Losses of preservative due to degradation and absorption in rubber-closed multiple-dose vials were investigated. The preservatives evaluated were benzyl alcohol, phenylethyl alcohol, p-chloro-β-phenyletbyl alcohol, chlorobutanol, and methylparaben. The elastomer closures used in this study were intended to be representative of those most commonly employed for pharmaceuticals and were natural, neoprene, and butyl rubbers. The temperature dependency of the degradation and diffusion processes were studied. An attempt was made to correlate preservative loss and microbiological activity.

The influence of several pharmaceutical materials on the fading of the certified color, FD&C Blue No. 2, has been investigated. It has been found that sugars such as dextrose, lactose, and sucrose increase the rate of fading, whereas sugar alcohols such as mannitol and sorbitol do not appreciably affect the rate. However, if trace amounts of strong reducing catalysts remain in the sugar alcohol after being crystallized, they significantly affect color stability. In general, antioxidants such as hydroquinone, p -hydroxypropiophenone and hydroquinone monomethyl ether were found not to appreciably retard the fading due to reducing sugars. In the case of NDGA, however, the rate of fading due to dextrose is substantially reduced. It appears that the rate of fading of the above color is catalyzed in the presence of reducing compounds.

A novel and accurate procedure for measuring the horizontal and vertical centration of tablet core in compressed coated tablets is described. This method of measurement permits the determination of core dislocation along and across the axis of turntable movement. The influence of size distribution of the coating granulation on core expansion and centration was studied. Results are presented for compressed coated tablets processed under similar operating characteristics on the Manesty and Kilian machines. A statistical treatment of the data was performed to permit a more meaningful interpretation and comparison of the results within one machine as well as between machines. This method for measuring core centration permits the determination of the size distribution of granulation necessary to give optimal centration.

The photosensitivity of a number of commonly used, certified water-soluble dyes employed in tablets has been investigated. Exposures were made under both normal and exaggerated light intensities. In both cases the spectral character of the radiation was similar. The dyes evaluated included FD&C Red No. 1, FD&C Red No. 3, D&C Green No. 5, FD&C Green No. 3, FD&C Blue No. 2, FD&C Blue No. 1, FD&C Yellow No. 5, D&C Yellow No. 10, D&C Orange No. 3, and FD&C Violet No. 1. Apparent rates of fading for the several dyes were determined. The relationship between fading and dye structure as well as fading and light intensity is discussed. The extent of dye fading beneath the surface of the tablet was also measured.

Manipulation of the Clapeyron-Clausius equation for solubility and freezing point depression resulted in a mathematical expression for the calculation of eutectic temperatures. Using this expression, the numerical estimation of the eutectic temperature in the implicit function was programmed in Fortran II on an IBM 1401 (8K) computer. Since the eutectic temperature is a function of the differential heat of solution, Lf ′, and melting point of a material, the program was written in a more general form to include values of Lf ′ from 100 to 6000 cal. and melting points from 10 to 300°. With this program, tables of eutectic temperatures in this region were printed.

The design and utilization of a light stability cabinet for testing pharmaceuticals has been described. The lighting system developed for this cabinet is intended to simulate ordinary room illumination found in the pharmacy, home, doctor's office, or in other storage areas for pharmaceuticals, but under accelerated light intensity. The use of this equipment eliminates the influence ox certain wavelengths in the ultraviolet spectrum of artificial sunlight testing equipment presently in use. Several representative pieces of artificial sunlight testing equipment used in the textile and dye industries are discussed. The photosensitivity of two tablet preparations were studied utilizing the specially designed light stability cabinet. Samples were stored in an open dish and in amber bottles. In one case the tablets contained a sulfonamide which darkened, while the other tablets contained a benzothiadiazine derivative plus D&C Orange No. 3 which showed fading of the color with storage. It was demonstrated that the amber glass appears to inhibit the deleterious effects of light on the tablets.

The kinetics of the hydrolysis of methyl DL-α-phenyl-2-piperidylacetate in aqueous buffers were studied over the pH range 1.1 to 6.1. The hydrolysis appears to be catalyzed specifically by hydronium and hydroxyl ions. The resulting catalytic catenary afforded a pH minimum of 2.86 at 80°. The pseudo first- and second-order velocity constants for hydronium and hydroxyl ion catalysis were determined, and the temperature dependency of the reaction was studied. The influence of ionic strength on the hydronium and hydroxyl ion catalysis was investigated. The structural characteristics of the molecule contributing to the isocatalytic point are discussed.

A description is presented of the circuitry, design, and operating characteristics of a temperature-conductivity bridge especially fabricated for eutectic and freezing-point temperature measurements. The resistance bridge is capable of measuring accurately from 10 3 to 10 12 ohms over a temperature range from −50° to +50°. A d.c. applied potential of 1, 10, or 100 v. is used as a power supply, and a solidstate operational amplifier is employed as the detecting system. By employing a high-gain amplifier with an input impedance in excess of 10 8 ohms, stable power supplies, and special insulation design, it is possible to cover the range from 10 3 to 10 12 ohms in narrow- or wide-range decade steps. The circuitry of the temperature-conductivity plotter permits temperature measurement by either thermocouple or thermistor circuits. The information obtained is displayed on a X - Y recorder with variable sensitivity.

This report demonstrates the protective action of Teflon linings on the sorption and leaching characteristics of polyurethan and natural rubber stoppers. This lining was effective in essentially eliminating extractives from appearing in water, 50 per cent polyethylene glycol 300, 50 per cent N , N -dimethylacetamide, 10 per cent ethanol, and 2 per cent benzyl alcohol when these solvents were in contact with the closures for 6 hr. at 115°. Sorption of the preservative, p -chloro- β -phenylethyl alcohol, from aqueous solution was effectively retarded by the Teflon lining on the stoppers. Reduced protection against sorption and leaching was found when Teflon lined closures, which previously underwent multiple puncture with a 20-gauge hypodermic needle, were used.

A series of in vitro experiments was performed to demonstrate the interdependence of physiologic surfactant and drug particle size on the dissolution rate of glutethimide, griseofulvin, and a new diuretic Compound A. The presence of physiological concentrations of lysolecithin (a naturally occurring biosurfactant) is shown to exhibit micellar solubilizing properties on the drugs investigated. The data obtained from the dissolution rate studies showed that aqueous lysolecithin solution caused significant enhancement of the extent of solution of the drugs investigated. However, the reduction of particle size through micronization may not necessarily increase the in vitro dissolution rate. Data to support this statement are presented, and a plausible explanation for its occurrence is the electrostatic charge that develops on the solids after milling. This results in aggregates which can be larger in particle size than the unmilled drug.

The influence of particle size distribution, particle shape, apparent bulk density, moisture content, additives, and punch shape on the directly compressible characteristics of potassium chloride were investigated. The relative weight and drug variability of hydrochlorothiazide-potassium chloride tablets prepared by direct compression were compared with those prepared by customary wet granulating techniques.

The influence of temperature and pH on the surface color and total dye content of tablets colored with selected dyes was studied. The representative dyes included were FD&C Red No. 4, Blue No. 1, and Yellow No. 5. Samples of tablets colored with these dyes and buffered at several pH levels were stored at elevated temperatures and tested for both residual dye concentration and fading at their surface. FD&C Red No. 4 was found to be the most stable of the three dyes tested. However, from the results of this study there appears to be no correlation between the fading at the surface of the tablets and the loss in colorant concentration at elevated temperatures.

The design and operation of a programmed automated tablet coating process 1 is described. The electronics of the programmer, the baffle design for the coating pan, and die spray equipment used are illustrated and discussed. The advantages and superiority of this process as compared with the customary manual coating techniques are presented.

The tetramethyl-substituted amides of pimelamide, suberamide, azelamide, and sebacamide markedly enhance the solubility of glutethimide in aqueous solution. Partition studies, surface tension measurements, and light-scattering measurements strongly suggest that the amides are associating at infinitely dilute concentrations and further aggregation of these associated molecules occurs with the possible formation of micelles at concentrations slightly higher than that observed for surfactants. The CMC' s were identified at 0.41, 0.20, 0.031, and 0.11 M for pimelamide, suberamide, azelamide, and sebacamide, respectively. The solubility of glutethimide was increased significantly above the critical concentrations and, from the nature of the solubility curves, a micellar type of solubilization appears to be dominant.

The data illustrate that a relationship exists between the eutectic temperature and solubility of several inorganic salts. The greater the effect of temperature on solubility, the higher the eutectic point. The influence of the anion of various salts of a particular cation on the eutectic temperature is demonstrated. Through resistivity-temperature measurements, it is possible to determine the eutectic and freezing points on a single curve. The influence of an inorganic salt on the freezing and thawing characteristics of an antibiotic solution was demonstrated.

The loss of benzyl alcohol, phenylethyl alcohol, and methylparaben from solution in the presence of natural, neoprene, and butyl rubber stoppers was studied. The influence of closure extractives on the analysis for residual preservative was evaluated. To insure valid determinations of preservative loss, techniques for eliminating the interference of extractives in the analysis were investigated. Partition studies were performed on the preservatives to determine their relative preference for each rubber composition studied.

Compressed coated tablets were prepared on a Manesty machine from four granulations of the same formulation, each having a granule of different size as its major component. The effect of granulation size on the weight variability of tablets was determined. The coating granulation sizes which give minimum and maximum weight variability are illustrated and are shown to be reproducible. The relationship that exists between weight variation and core centration is discussed.

The influence of conventional lactose and spray-processed lactose and their primary hydrolysis products ( d -glucose and ( d -galactose) on the stability of various certified colorants has been investigated. Spectrophotometric and paper partition chromatographic examination indicated that in aqueous buffered solutions (pH 6.6 to 6.8), FD&C Red No. 4, FD&C Yellow No. 5, FD&C Green No. 3, and FD&C Blue No. 1 are relatively stable when exposed to exaggerated lighting and temperature in the presence of these sugars. FD&C Blue No. 2 was found to be very unstable, particularly when exposed to light, and the sugars significantly accelerate the decomposition of this color. The decomposition of FD&C Blue No. 2 appears to proceed by reduction to a semiquinone followed by oxidation. There appears to be some evidence to indicate molecular changes in the lactose when stored at high temperature. These changes appear to interfere with the spectrophotometric analysis of colorants which absorb between 228 m μ and 284 m μ.

Previous reports indicate that there is a marked increase in the rate of solution of most materials that have been lyophilized. Thus, this investigation was undertaken to determine whether several pharmaceutical gums and suspending agents, which are not readily soluble or dispersible in water, would be more rapidly soluble or dispersible in the lyophilized state. Data are presented showing that the rate of solution or dispersion of sodium carboxymethylcellulose 70 L, 70 M, 120 M, 120 H, Veegum, Veegum H.V., Carbowax 6000, acacia, tragacanth, sodium alginate, bentonite, agar, gelatin, pectin and Clear Flo-H starch are markedly increased after lyophilization. For the majority of the compounds studied, no significant change in viscosity or pH was observed when the lyophilized material was reconstituted.

The water vapor transmission of thin plasticized cellulose acetate phthalate films was studied at 90, 76, and 52 per cent relative humidities. The effect of the plasticizers, triacetin, diacetin, diethyl phthalate, dimethyl phthalate, Citroflex-2, Citroflex-A2, and dibutyl tartrate on this property was determined. In general, a decrease followed by an increase in water vapor transmission was observed with increasing plasticizer concentration. The concentration at which the water vapor transmission is at a minimum appears to be the same for all the plasticizers investigated.

An accurate and rapid microbiological method for assaying chemical preservatives of nonantibiotic nature has been developed which employs a time-tested, proven procedure. Preservative concentration is measured by a turbidimetric procedure using Escherichia coli as the test organism. The method has been applied to chloro-butanol, phenol, and -chloro-beta-phenylethyl alcohol and compares favorably with chemical analytical methods.

In the preparation of solutions containing quaternary ammonium compounds and certified dyes, it was found that precipitation or clouding resulted in several solutions. A phase study between several quaternary ammonium compounds and dyes has been performed to determine the concentration relationship needed to cause precipitation of the reacted species. Phase diagrams are presented for the systems cetylpyridinium chloride-dye, benzalkonium chloride-dye, and dodecyldimethyl (2-phenoxyethyl) ammonium bromide 1 -dye. Three certified dyes, D&C Yellow No. 10, FD&C Red No. 1, and FD&C Blue No. 1 were used with each quaternary ammonium compound. These phase diagrams indicate the areas of physical compatibility and incompatibility.

A synthetic caffeine homolog, 1-ethyltheo-bromine, has been shown to complex with benzocaine. Although this interaction differs from that of caffeine in a number of respects, the results indicate that 1-ethyltheo-bromine is also effective in decreasing the rate of hydrolytic breakdown of the drug through complex formation.

The loss of preservative content due to degradation in solution and absorption by rubber stoppers was studied by chemical and microbiological analytical methods. The preservatives investigated were chlorobutanol and p -chloro- β -phenylethyI alcohol in conjunction with neoprene rubber stoppers. The contribution of rubber extractives and preservative degradation products towards enhanced antimicrobial activity is discussed.

The relationship that exists between the discoloration of spray-processed lactose and the presence of 5-(hydroxymethyl)-2-furaldehyde (HMF) was investigated. The HMF was determined by reaction with 2-thiobarbituric acid using procedures developed by Keeney and Bassette. The results obtained indicate that spray-processed lactose contains significant quantities of HMF, while conventionally processed lactose contains essentially no HMF.

The literature reports on the subject of interunit dosage and weight variations of tablets indicate that past studies were mainly concerned with analyzing the finished product to detect gross departures from the desired quality. These studies, however, were cognizant of the several stages of manufacture before the compression step could contribute to the end tablet variability. In this investigation, the variability in several stages of tablet manufacturing (dry mixing, granulating, lubricating, and tableting) was evaluated for a particular tablet formulation. The importance of employing correct sampling procedures to obtain random samples to be used for the accurate estimation of the sources of variability and product uniformity is illustrated. The relationship that exists between tablet weights and drug concentration was determined. Since systematic sampling is commonly employed in the in-process control of tableting operations, the information that can be gained from this type of sampling procedure and random sampling is presented and discussed.

A study of the tetracaine hydrochloride-caffeine system has shown that the hydro-lytic rate of the ester component is reduced in the presence of the xanthine in a manner similar to that of the benzocaine-caffeine and the procaine hydrochloride-caffeine systems. Evidence seems to indicate however, that the stoichiometry of the complexing reaction is different from the previous cases. The data obtained are best rationalized on the basis that tetracaine ion forms two types of complexes in solution, the first consisting of two caffeine molecules to one tetracaine ion and the second of two tetracaine ions to one caffeine molecule. According to the present findings, addition of one-half per cent caffeine to a similar concentration of tetracaine hydro-chloride in water, for example, reduces the hydrolytic rate by thirty-five per cent. In the presence of two per cent caffeine, the rate of hydrolysis is only one-third that of the caffeine-free solution.

Four tablet formulations made from two types of lactose were studied. The granulations were compared for particle size distribution, flow properties, and moisture content. The tablets made from them were evaluated for hardness, friability, disintegration time, weight control, and color development at room temperature, 40°, 50°, and 60° for 12 weeks. In general, it was found that spray-dried lactose produced harder, less friable tablets which, however, were more susceptible to color development following storage at elevated temperatures.

A holder which permits the centering and leveling of individual tablets in the reflectance attachment of the Beckman model DU spectrophotometer is described. By this adaptation, it is possible to measure the reflected light from the upper or lower surface of a tablet with a precision of two per cent. This method of measurement has proved useful in assigning reproducible numerical values for the light reflected from tablets.