Assessment of the Myotoxicity of Pharmaceutical Buffers Using an In Vitro Muscle Model: Effect of pH, Capacity, Tonicity, and Buffer Type

Abstract

The purpose of the present study was to investigate the myotoxicity of three buffers containing carboxylic acid groups (i.e., acetate, succinate, and citrate) as a function of their pH, capacity, and tonicity. The myotoxicity of these buffers in the range of pH 2-6 and 0.001-0.1 M buffer capacity was assessed using cumulative creatine kinase (CK) release from an isolated rodent muscle model following injection. Phenytoin and 0.9% NaCl injection were used as positive and negative controls, respectively. Buffer solutions were prepared. A lower pH and higher buffer capacity was linked to increased myotoxicity for the acetate buffers. However, for succinate and citrate buffers, pH appeared to influence the extent of myotoxicity, whereas buffer capacity did not seem to have an effect. When either NaCl or trehalose was used as a tonicity-adjusting agent at pH 6, isotonic 0.01 M buffer solutions dramatically lowered the cumulative CK release compared to those that were not isotonic. Isotonic succinate buffers displayed the lowest myotoxicity, whereas citrate buffers displayed the highest values. Citrate buffers containing three carboxylic acid groups showed higher myotoxicity than succinate buffers and acetate buffers at 0.001 and 0.01 M buffer capacities, whereas acetate buffer produced higher cumulative CK release than citrate and succinate buffers at 0.1 M buffer capacity. The myotoxicity of pharmaceutical buffers containing carboxylic acid groups appears to be directly affected by lowering the pH of the solution.

Lethal outbreak of infection with Clostridium novyi type A and other spore-forming organisms in Scottish injecting drug users

“…The acidic solution devitalised the tissue [15], thus favouring the propagation of anaerobic infection. Toxin production led to the development of a severe localised inflammatory reaction with marked oedema which, in some cases, was followed by a life-threatening systemic illness, characterised by hypotension, a leukaemoid reaction and necrotising fasciitis.…”

Potential Use of Cyclodextrins to Enhance the Solubility of YM466 in Aqueous Solution

“…It is reported that citrate buffer can induce myotoxicity, which might cause local irritation after administration. [8] To reduce this possibility, lactate buffer may be more suitable. Furthermore, the inclusion of YM466 with CDs may reduce local irritation.…”

Pharmacokinetics for Medicinal Chemists

“…An ideal formulation for IV administration should contain only water and water-soluble components (salts, buffers). The acceptable range of pH for the IV formulation may be expanded with the use of a lower dosing volume but must be balanced with the in vivo tolerability requirements [47]. The acceptable pH range for IV formulations may vary from 2 to 12 [44].…”