D.J.W. Grant

The influence of processing variables on the wetting properties of a hydrophobic powder

Abstract The aqueous wetting properties of samples of a hydrophobic powder (griseofulvin) prepared by crystallisation, controlled precipitation, dry grinding and wet grinding have been assessed by two methods in terms of a contact angle, θ. The first employs drop formation on the surface of compacted powder, previously saturated with solution, while the second employs extrapolation of the quantity, cos θ, obtained for penetration of ethanol—water mixtures into powder beds, to zero mole fraction of ethanol concentration. Both methods establish that a difference exists in the surface properties of the different samples of powder and this appears to be a function of the process rather than the batch of powder. The two methods give significantly different values for the aqueous contact angle, which appears to be related to the actual nature of angle measured. The value derived from liquid penetration appears to provide a better reflection of the properties of the powder samples.

The release of a model low-dose drug (riboflavine) from hard gelatin capsule formulations

The in vitro release of a model low dose drug, riboflavine, from hard gelatin capsules, formulated with a range of diluents, in the absence and presence of magnesium stearate (0.5, 1.0 and 2.0% w/w), has been assessed by a dissolution technique. Comparison of the values of the time for 50% of the drug content of the capsule to appear in solution T50, by analysis of variance, indicated that the type of diluent significantly influenced the drug release. Irrespective of the magnesium stearate content, the diluents could be ranked in the following order of effectiveness: Primojel > sodium bicarbonate > Avicel ≃ Dri‐flo starch ≃ lactose > Emcompress ≃ kaolin > starch. Correction of the T50 values for possible adsorption of riboflavine onto the water insoluble diluents, using experimentally determined adsorption isotherms, altered the relative order of effectiveness of the diluents to Primojel > sodium bicarbonate > kaolin ≃ lactose > Avicel ≃ Dri‐flo starch > Emcompress > starch. Comparison of the urinary excretion of riboflavine, after administration of capsule formulations containing lactose, Emcompress or kaolin as the diluent, to volunteers, suggests that the dissolution results not corrected for adsorption provide a better indication of the in vivo performance of the formulations.

Influence of physicochemical interactions on the properties of suppositories V. The in vitro release of ketoprofen and metronidazole from various fatty suppository bases and correlations with in vivo plasma levels

Abstract Various membrane and non-membrane methods of in vitro measurement of drug release from suppositories were examined from a literature survey and using 200 mg fatty suppository formulations containing 7.4 mg of ketoprofen or 46 mg of metronidazole. The fatty suppository formulations differed in the bases, which were either commercial bases or binary mixtures of pure triglycerides. Rotation about various axes of a cylindrical cell fitted with a membrane at each end gave essentially the same in vitro release profile provided that the molten base did not coat the membrane surface. Linear correlations between the drug concentration released in vitro and the in vivo levels in plasma at given time intervals after administration of various suppository formulations to rats were generally not statistically significant. On the other hand, comparison of these in vivo data with the non-membrane in vitro results using rank order correlation methods on paired data at each time interval for a number of suppository formulations showed statistically significant correlations. Although plastic viscosities did not correlate with in vitro release, the base with the lowest viscosity always gave the fastest release of either drug. On balance, non-membrane methods of measuring in vitro drug release are generally favoured.

PREFORMULATION STUDIES ON INGREDIENTS OF SUPPOSITORY BASES

Fatty suppository bases are complex mixtures of triglycerides. In order to study the physico-chemical interactions within s~PPositories, especially interactions between the drug and the excipient, it is desirable initially to simplify the system. This may be achieved by examining binary mixtures of pure monoacid triglycerides to obtain a composition whose characteristics resemble those of commercial bases. An explanation for increases in melting point observed on storage of suppositories is proposed here.

A synthetic method for determining the solubility of solids in viscous liquids

Abstract Measurement of the solubility of a solid in a viscous liquid at a predetermined temperature using an analytical method poses problems on account of the difficulty of removing excess of the suspended solid from the viscous solution at constant temperature. As an alternative, a simple synthetic method is proposed involving measurement of the temperature at which a stirred solute-solvent mixture of predetermined composition just forms a homogeneous solution. By means of this the equilibrium solubility temperature can be quickly bracketted to 1°C. From the solubility-temperature data thus obtained, ΔG, ΔH and ΔS for the solution process may be readily calculated. Furthermore, physicochemical interactions between a solid drug and a molten excipient may be studied at regions of composition in which other thermal methods of analysis may not be suitable.

Inhibitory effects of some antiinflammatory and other analgesics and nitrofurans on the induction of β-galactosidase synthesis in Klebsiella aerogenes

Abstract The effects of the following drugs were studied on the induction of β-galactosidase synthesis by and the growth of Klebsiella aerogenes : acetylsalicylic acid (I), salicylic acid (II), salicylamide (III), diacetylpyrocatechol-3-carboxylic acid (Movirene, IV), ibufenac (V), ibuprofen (VI), paracetamol (VII), phenacetin (VIII), morphine (IX), nalorphine (X), nitrofurazone (XI), nitrofurantoin (XII), furazolidone (XIII), oxine (XIV), nitroxoline (XV), niridazole (XVI). The antimicrobial compounds XI–XVI inhibited enzyme induction at low concentrations and were even more active against growth which was preceded by a lag. The analgesics I–X reduced the growth rate but did not give a lag and were more active against enzyme induction. The anti-inflammatory antipyretic analgesics I–VI inhibited enzyme induction at concentrations of the same order as those which inhibit nociception and inflammation in mammals. The non-anti-inflammatory antipyretic analgesics VII and VIII inhibited enzyme induction at higher concentrations and the narcotic analgesic IX and its antagonist X inhibited enzyme induction at concentrations about 100 times those which inhibited nociception. IX did not antagonise the inhibitory effects of X and vice-versa . The inhibitory effects of I can be ascribed to II produced by hydrolysis. There is a general parallelism between inhibition of enzyme induction and anti-inflammatory activity, which is discussed and related to current theories of anti-inflammatory action. Inhibition of protein synthesis is suggested to be a primary biochemical effect leading to anti-inflammatory properties. Testing for the ability to inhibit induced enzyme synthesis by bacteria may be useful in screening drugs for anti-inflammatory properties.

Influence of phystcochemical interactions on the properties of suppositories IV. Factors influencing the in vivo release of ketoprofen and metronidazole from fatty suppository bases

Abstract The advantages and disadvantages of animal models employed for the testing of suppositories in vivo are discussed and the rat has been selected for the present work. Some of the important variables involved in these tests have been investigated using fatty suppositories consisting of binary mixtures of pure mono-acid triglycerides. The drugs employed, ketoprofen and metronidazole, give solution and suspension suppositories, respectively. Using Kendalls method of rank correlation, the bioavailability of ketoprofen or metronidazole has been found to correlate significantly with the rate of spreading of fatty suppositories but not with the plastic viscosity of the base, determined in a rotational viscometer. Accurate prediction of the plots of drug plasma levels vs time from individual mean data points from a number of rats is found to be difficult as reflected by the wide 95% confidence limits. The main use of such plots is to indicate trends. The highest blood level profiles for both the solution and suspension suppositories are found to be given by formulations containing the binary triglyceride mixture consisting of 60% w/w tricaprin and 40% w/w trilaurin as constituents of the base.

Removal of hydrophobic surface coatings from a non‐disintegrating hydrophilic solid in a water stream

FEE, J. V., GRANT, D. J. W. & NEWTON, J. M. (1973). J. Pharm. Pharmac., 25 Suppl., 148P-149P. LEVICH, V. G. (1962). Physicochemical Hydrodynamics. Englewood Cliffs, N. J., U.S.A. : Prentice-Hall. NERNST, W. (1904). ZDANOVSKII, A. B. (1951). Zhur. Fiz. Khim., 25, 170-179; through Chemical Abstracts, (1954). 48, 4291c. * Present address : Royal Infirmary of Edinburgh, Edinburgh. Z. Physik. Chem., 47, 52-55.

A method of testing the applicability of the diffusion layer dissolution model

& others, 1973) thus hindering steroid incorporation. AGO also increased with increased steroid polarity. The steroids interacted exothermically with the surfactants. AS was negative for hydrocortisone and dexamethasone and became positive for the less polar testosterone and progesterone. Two opposing factors account for this. (1) Crowding of the solubilized steroid in the micelle occurs with negative entropy change. (2) Configuration entropy of the solubilized molecules increases due to the breakup of the water structure surrounding nonpolar hydrocarbon molecules or groups. Effect 1 governs the solubilization of hydrocortisone and dexamethasone while effect 2 controls that of testosterone and progesterone. BRITISH PHARMACEUTICAL CONFERENCE 1974 :