Solving manufacturing problems for L-carnitine-L-tartrate to improve the likelihood of successful product scale-up

Abstract

L-carnitine-L-tartrate, a non-essential amino acid, is hygroscopic. This causes a problem in tablet production due to pronounced adhesion of tablets to punches. A 3 3 full factorial design was adopted to suggest a tablet formulation. Three adsorbents were suggested (Aerosil 200, Aerosil R972, talc) to reduce stickiness at three concentrations (1, 3 and 5 %), and three fillers (mannitol, Avicel PH 101, Dibasic calcium phosphate) were chosen to prepare 27 formulations. Micromeritic properties of formulations were studied, and tablets were prepared by wet granulation. Absence of picking, sticking or capping, recording of sufficient hardness, acceptable friability and tablet ejection force indicated formulation success. The resulting formulation prepared using Avicel PH 101 and 1 % Aerosil 200 was submitted to further investigation in order to choose the most suitable compression conditions using a 3 3 full factorial design. Variables included compression force, tableting rate and magnesium stearate (lubricant) concentration. The formulation prepared at compression force of 25 kN, using 2 % magnesium stearate, at a production rate of 30 tablets/ minute, was found to be the most appropriate scale up candidate.Keywords: L-carnitine-L-tartrate, adsorbent, scale-up, compression force, ejection force, hygroscopicCarnitine is a non-essential amino acid derivative and a cofactor of fatty acid metabolism in the heart, liver and skeletal muscle (1). It was designated vitamin Bt but is not an officially recognized vitamin (2). It is found primarily in animal products such as meat (principally red meat), fish, poultry (2). In humans, the liver, brain and kidney synthesize carnitine (3, 4). Carnitine is an endogenous mitochondrial membrane compound (5) and its deficiency results in disordered membrane transport (1, 2). L-carnitine is a ((R)-(3-carboxy-2-hydroxypropyl) trimethylammonium hydroxide inner salt) (6). It occurs in two distinct stereoisomers, namely, L-carnitine (naturally occurring carnitine, which is biologically active) and D-carnitine (synthetic carnitine, which is biologically inactive) (7). L-carnitine is a white or almost white crystalline powder or comes in the form of colorless crystals, hygroscopic and freely soluble in water. It is soluble in warm ethanol (96 %) and practically insoluble in acetone, ether and benzene (8, 9). L-carnitine was formulated easily into liquid preparations such as an oral solution and i.v. injection. Due to its hygroscopicity, its formulation into capsules is not preferred (10), as the stability of the capsule shell is affected (11).Formulation of L-carnitine-L-tartrate into tablets offers many advantages over hard gelatin capsules. Tablets can contain a relatively high dose of L-carnitine-L-tartrate, mainly 485.3 mg, which is equivalent to 330 mg of L-carnitine base. Also, tablets enable the use of many excipients in quantities sufficient to overcome the adverse effects of L-carnitine-L-tartrate hygroscopicity on tablet properties.Many problems are expected during the formulat...

Stabilisasi Tablet yang Mengandung Zat Aktif Bersifat Higroskopis

“…Selain itu, penggunaan kemasan alumunium menunjukkan kekerasan yang lebih baik pada uji stabilitas dibandingkan dengan tablet yang dikemas menggunakan PVDC. F. Nurjanah,Majalah Farmasetika,6 (1) 2021, [10][11][12][13][14][15][16][17][18][19][20][21][22]…”

One Factor at a Time and factorial experimental design for formulation of l-carnitine microcapsules to improve its manufacturability

“…Among the solutions suggested was using a less hygroscopic l -carnitine salt as l -carnitine tartrate [ 13 ]. Also, the use of adsorbents to adsorb moisture, thus stabilizing l -carnitine [ 14 ]. Drug encapsulation can represent a barrier separating the hygroscopic drug from the moisture.…”