Parenteral nutrition. Pharmaceutical problems of compatibility and stability.

A typical All-in-One (AIO) parenteral nutrition mixture in a 3-litre polymeric infusion bag will consist of lipid emulsion, amino acids, glucose, electrolytes, trace elements and vitamins. This varied mixture of chemical entities provides the potential for a number of chemical and physicochemical interactions that can compromise the clinical safety and efficacy of the product. The destabilisation of the lipid emulsion in the presence of electrolytes is a major problem. Although a predictive equation for the maximum concentrations of mono-, di- and trivalent ions causing instability has been proposed, it is too simplistic to be of significant value. The reasons for this are discussed as well as the stability implications of other additives to the parenteral nutrition mixture.

PARSAFE: computer program for safety assessment and optimization of parenteral nutrition formulations based on chemical speciation analysis.

Instability arising from the formation of precipitates and lipid emulsion aggregates is common in parenteral nutrition formulations due to the concentration- and pH-dependent incompatibility of some of the vital ingredients. Previously, the boundaries between stability and instability could only be established through the use of laborious and expensive empirical methods. The predictive technique with the concept of chemical speciation (based on the analysis of many competitive thermodynamic equilibriums) has been adapted for use with parenteral fluids so that these detrimental events may now be avoided. A comprehensive computer program, PARSAFE ((C) 1991. Sponsors interested in this program should contact D.R.W.) has been developed for this purpose. PARSAFE encompasses chemical-speciation techniques and contains a large data base of commonly used intravenous fluid constituents together with the appropriate thermodynamic equilibrium constants describing their interactions so that stability prediction may be readily achieved in hospital pharmacy laboratories. We review the relevant physical chemistry required for the successful implementation of PARSAFE and outline the audit trails involved in the development of the predictive model.

Studies on powder plug formation using a simulated capsule filling machine.

Using an apparatus which simulates the action of a Macofar 13-2 dosating-type capsule-filling machine, the variation in plug weight and density with changing machine parameters has been studied. The piston ejection speed has no effect on plug properties. However increase in compression speed leads to a less consolidated powder plug and hence reduced plug weight. Application of higher pressures reduces plug weight changes, but would be expected to affect release characteristics. Comparison of axial and radial pressures generated by plugs of Starch 1500 and lubricated lactose show significant differences which can be explained by the different consolidation and elastic properties of the two solids.

Dissolution rate measurements of sparingly soluble compounds with the Coulter Counter model TAII.

A Coulter Counter, Model TAII was used to determine both solubility and dissolution rate from suspensions of griseofulvin and hydrocortisone acetate, where the initial particle size and shape had been characterized. The method assesses the weights and surface areas of particles remaining undissolved as a function of time. A comparison with a conventional method, assessing dissolved quantities of materials, showed that solubility data of the same order of magnitude can be obtained. The TAII data fitted a previously established equation that linearly relates log solubility and log of the intrinsic dissolution rate and indicated that the dissolution process was not diffusion controlled. The TAII method described is a rapid and convenient means of estimating the solubility and dissolution rate where no adequate technique for analysing the dissolved fraction exists.

Construction of an intermittent-motion capsule filling machine simulator.

A pneumatically operated apparatus is described which simulates the forces generated by and the component movements encountered in a Macofar 13/2 dosator type capsule filling machine. Force transducers are fitted to the dosing piston and dosator tip, and the movement of the dosator piston and the powder bed followed by displacement transducers. Calibration of the transducers is described. The output from the transducers is collated, stored and manipulated by microcomputer. The manufacturing parameters which can be studied using this apparatus are discussed.