Barry Arnold Hendriksen

The composite solubility versus pH profile and its role in intestinal absorption prediction

The purpose of this study was to examine absorption of basic drugs as a function of the composite solubility curve and intestinally relevant pH by using a gastrointestinal tract (GIT) absorption simulation based on the advanced compartmental absorption and transit model. Absorption simulations were carried out for virtual monobasic drugs having a range of pKa, log D, and dose values as a function of presumed solubility and permeability. Results were normally expressed as the combination that resulted in 25% absorption. Absorption of basic drugs was found to be a function of the whole solubility/pH relationship rather than a single solubility value at pH 7. In addition, the parameter spaces of greatest sensitivity were identified. We compared 3 theoretical scenarios: the GIT pH range overlapping (1) only the salt solubility curve, (2) the salt and base solubility curves, or (3) only the base curve. Experimental solubilities of 32 compounds were determined at pHs of 2.2 and 7.4, and they nearly all fitted into 2 of the postulated scenarios. Typically, base solubilities can be simulated in silico, but salt solubilities at low pH can only be measured. We concluded that quality absorption simulations of candidate drugs in most cases require experimental solubility determination at 2 pHs, to permit calculation of the whole solubility/pH profile.

Crystallisation of paracetamol (acetaminophen) in the presence of structurally related substances

Paracetamol was crystallised from aqueous solutions containing various concentrations of structurally related compounds. Crystal shape was characterised by image analysis and the additive concentration incorporated into the crystals determined by HPLC. The crystal structure of pure acetaminophen displays a hydrogen bonded network, from which is derived a mechanistic interpretation of the abilities of additive molecules to influence crystal growth. This structural approach was used to explain the observed additive uptake, the morphological changes, and the previously reported inhibition of nucleation.

The effect of structurally related substances on the nucleation kinetics of paracetamol (acetaminophen)

Abstract A computer controlled and monitored apparatus is described in which supersaturation was induced in paracetamol solutions by cooling. The induction time before nucleation occurred was determined by the attenuation of a laser beam which passed through the solution. Certain additives, particularly p-acetoxyacetanilide (PAA) (2–4 mol%), caused significant inhibition of nucleation. The induction time was expressed as a function of the supersaturation and absolute temperature, leading to estimates of the interfacial tension between the solution and the critical nucleus in the presence and absence of the additives, and to estimates of the number of molecules comprising the critical nucleus.

A new multiwavelength spectrophotometric method for the determination of the molar absorption coefficients of ionizable drugs

ABSTRACT A multiwavelength spectrophotometric method, called Dip-Probe Absorption Spectroscopy (D-PAS), developed previously for pKa determination was applied for the determination of the molar absorption coefficients of ionizable compounds. Specifically, the spectral data obtained from a spectrophotometric titration are resolved using Target Factor Analysis (TFA) to generate the molar absorption coefficients of each ionizing species. The D-PAS method has been exemplified by the spectral data of p-aminosalicylic acid and nicotinic acid. It has been shown that the molar absorption coefficients as determined by the D-PAS method are comparable to those deduced by manual titration experiment.