Solid State Stability and Preformulation Studies for Acetylcholinesterase Inhibitor Drug Tacrine

Denisa Circioban,Ionuț Ledeți,Gabriela Vlase,Adriana Ledeți,Titus Vlase

doi:10.35995/tmj20200104

Abstract

In this paper, the acetylcholinesterase inhibitor drug tacrine was investigated by two complementary instrumental techniques, namely infrared spectroscopy and thermal analysis, as pure drug and in solid binary mixtures with nine excipients frequently used in the pharmaceutical industry, namely starch, sodium carboxymethyl cellulose, polyvinylpyrrolidone K30, fumed silica (Aerosil), talc, anhydrous lactose, magnesium stearate, mannitol and calcium lactate pentahydrate. The corroboration of obtained data by the two complementary methods confirmed the incompatibility of this drug with anhydrous lactose, mannitol, magnesium stearate and calcium lactate under both ambient conditions and thermal stress, and thermally induced interactions between tacrine and silica. In the development of new generic solid formulations, four of the investigated excipients (i.e., starch, sodium carboxymethyl cellulose, polyvinylpyrrolidone K30 and talc) can be used, since they are compatible with tacrine under ambient conditions as well as under thermal stress.

Highlights

Alzheimer’s disease (AD) or Alzheimer’s dementia was first characterized at the beginning of the 20th century by Dr Alois Alzheimer
The selected excipients were of pharmaceutical grade, suitable for use in solid formulations: calcium lactate (CaL, Aldrich, Steinheim, Germany), mannitol (Man, Merck, Darmstadt, Germany), magnesium stearate (MgSt, Union Derivan, Barcelona, Spain), anhydrous lactose (LAnh, Merck, Darmstadt, Germany), talc (T, Luzenac Pharma, Porte, Italy), fumed silica (SiO2, Aerosil 200, Evonik Degussa, Essen, Germany), polyvinylpyrrolidone K30 (PVP, Sigma-Aldrich, Steinheim, Germany), sodium carboxymethyl cellulose (NaCMC, Sigma-Aldrich, Steinheim, Germany) and starch (St, Grain Processing Corporation, Muscatine, IA, USA)
Two investigational instrumental tools were chosen for the compatibility evaluation of tacrine hydrochloride hydrate (TCR) with the selected excipients in ambient conditions and under thermal stress, namely UATR-FTIR spectroscopy and thermoanalytical investigations

Summary

Introduction

Alzheimer’s disease (AD) or Alzheimer’s dementia was first characterized at the beginning of the 20th century by Dr Alois Alzheimer. The most common symptoms associated with this disease include progressive memory loss, disorientation, personality and mood changes, struggles while performing daily tasks, communication problems, poor judgement, sleep disturbances and difficulty recognizing family or friends. The literature mentions the reduction in acetylcholine (ACh) synthesis as the primary cause, since it was clinically observed that patients suffering from AD present with deterioration of cholinergic neurons and loss of neurotransmission that, in turn, lead to declined cognitive function. The pharmaceutical class of AChE inhibitors was developed [3]

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