The role of solid nanoparticle technology in the parenteral delivery of poorly water-soluble drugs.

Water insolubility has always been a key obstacle in pharmaceutical formulation, affecting formulation stability and drug bioavailability. Approaches for achieving complete dissolution often have disadvantages associated with the large quantities of required excipients. Small-particle suspensions (200 nm-2 microm), consisting essentially of pure drug, require only a minimum amount of surface-active agent for stabilization. Such suspensions may be formulated for rapid dissolution, thus achieving pharmacokinetic properties similar to those of a solution, or drug insolubility may be leveraged to afford prolonged in vivo release. In both situations, higher dosing may be possible than with a drug solution. This may afford enhanced efficacy at reduced excipient concentrations with potentially less toxicity. We present a brief introduction to the pharmaceutical technology of pure submicron drug particles in relationship to other dosage forms, and study examples are presented to underscore the potential benefits of this approach in parenteral delivery.

Computer simulation of the effect of temperature on pH.

The effect of temperature on solution pH was simulated by computer (program PHTEMP). We have determined that the change in pH due to shifts in acid-base equilibria [delta pH = pH(60 degrees C) - pH(25 degrees C)] can be substantial for compounds such as aliphatic amines that have high enthalpies for acid dissociation. This is of particular significance during elevated temperature experiments in which changes in the pKa values of formulation components, and hence the solution pH, can accelerate decomposition as compared to those formulations where sensitive functionality is absent. PHTEMP afforded the following results at initial pH = 7 (25 degrees C): (a) 0.1 M triethylamine (delta H zero = 10.4 kcal/mol) delta pH approximately -0.8; (b) 0.1 M acetic acid (delta H zero = -0.1 kcal/mol) delta pH approximately 0; (c) 0.1 M sulfuric acid (delta H zero 1 = -12 kcal/mol; delta H zero 2 = -5.4 kcal/mol) delta pH approximately -0.4. Solutions of general pharmaceutical interest were also studied and included a 12-component amino acid mixture, 0.1 M glycine, and 0.1 M triethylamine in either 0.02 M citric acid or 0.05 M TRIS buffer. In each case the pH change with temperature was dependent on the concentrations of components, the enthalpies for each acid dissociation, and the starting pH. At lower pH (< 4), PHTEMP predicts that delta pH is typically smaller than at higher pH (> 9). These results are interpreted as the effect of a relative change in hydronium ion activity, delta H+/H+(initial), due to temperature-induced shifts in equilibria (acid dissociation, water autoprotolysis). This relative change must become larger as H+ decreases (pH increases). The output of PHTEMP was experimentally verified with 0.1 M glycine and with a multiple component amino acid solution. In both cases, agreement with prediction was excellent. The results of this investigation underscore the need to critically review formulation choices for both thermodynamic and traditional kinetic effects on the resulting product stability.

Nonisothermal stability assessment of stable pharmaceuticals: testing of a clindamycin phosphate formulation.

The stability of an antibiotic formulation (clindamycin phosphate in dextrose), which is stable at room temperature, was assessed by nonisothermal kinetic analysis at elevated temperatures. A preliminary study, conducted to establish apparent rate order, verified the appropriateness of a first-order kinetic model. The test formulation was then heated linearly from 70 to 90 degrees C over 12 hr. Data (drug concentration, temperature, and time) were fitted to the first-order model using nonlinear least-squares regression. Arrhenius parameter estimates obtained from three nonisothermal trials, and rate constants at 25 degrees C derived by extrapolation, demonstrated acceptable reproducibility and were in agreement with values derived from isothermal experiments at 30, 45, 55, 65, and 75 degrees C. First-order rate constants obtained from studies conducted for 20 months at 25 degrees C were in accord with isothermal and nonisothermal results.