Artesunate and amodiaquine are incompatible, wherein severe degradation of the drugs in presence of each other. The central hypothesis for formulation development was based on the sensitivity of artesunate to the acidity brought by HCl molecules present in the amodiaquine salt that is enhanced by temperature and humidity. Due to the chemical incompatibility of the two drugs which causes mutual decomposition and leads to stability problems. This poses a challenge to the formulating pharmacist while presenting the combination of the two drugs in a single dosage form.

The objective of formulating a single dosage form is improved patient compliance resulting in decreased possibility of recurrence or developing resistance.

Different ways to solve the problem of incompatibility between the two active ingredients have been tested :
  1. Formulations of monolithic and multilayer tablet.
  2. Formulation two ingredients tablet in tablet.
  3. The formulation can also be presented as other solid dosage forms such as capsule, pills, granule, sachets and such like, in a mutually protected environment such as coated granules.
  4. Classical excipients : pH regulators and hydrophobic agents.
  5. Various manufacturing processes : dry granulation in order to limit the humidity content in the formulation. Impact of controlled temperature and humidity conditions.
A spesific analytical method for the determination of artesunate and its degradation products has been developed to assess the stability of the tablets.

Manufacturing of Artesunate and Amodiaquine Fixed Dose Combination Tablet in Tablet

Manufacturing Process
  1. Artesunate was granulated with acceptable excipients and compressed into tablet.
  2. Artesunate tablet was coated with film coated tablet for protection.
  3. Amodiaquine was granulated to form outer tablet.
  4. Artesunate coated tablets was compressed within amodiaquine granules so as to form core of Amodiaquine tablets by tablet in tablet technology.
Formulation

Artesunate Core Tablet
%Material
13.51Artesunate
6.89Mannitol
5.54Lactose
0.8Croscarmellose Sodium
0.27Hydroxypropyl Cellulose
qsIsopropyl Alcohol
0.81Crosecarmellose Sodium
0.13Colloidal Silicon Dioxide
0.13Magnesium Stearate
  1. The active ingredient and the diluents were blended together and passed through relevant sieves.
  2. The resultant blend was further granulated in a high shear mixer with the binder solution prepared by dispersing hydroxypropyl cellulose in isopropyl alcohol.
  3. After the wet mass was sized through suitable sieves, the solvent was evaporated from granulate by drying at 50-55°C to achieve the desired moisture content of the granules, determined by loss on drying.
  4. The dried granules were reduced by sizing through suitable sieves and lubricated, cross caramellose sodium, colloidal silicon dioxide and magnesium stearate were incorporated as lubricants to produce the final compression blend.
  5. The resultant lubricated granules were compressed into tablets, to a desired target on a suitable tablet press.
Film Coated Tablet for Artesunate
%Material
2.5Hydroxypropyl Methylcellulose
1.3Talc
0.67Titanium Dioxide
0.25Polyethylene Glycol 6000
qsIsopropyl Alcohol
qsMethylene chloride
  1. Artesunate tablets prepared were film coated in a coating pan with an appropriate non-aqeous/alcoholic Hydroxypropylmethylcellulose (HPMC) based film coat.
  2. This film coat is act as protective barrier for the core artesunate tablets to shiled artesunate from direct exposure to the outer amodiaquine as the two active ingredients are incompatible.
  3. Weight total for inner artesunate coated tablet is 220 mg.
Amodiaquine Granule
%Material
2.5Hydroxypropyl Methylcellulose
1.3Talc
0.67Titanium Dioxide
0.25Polyethylene Glycol 6000
qsIsopropyl Alcohol
qsMethylene chloride
  1. Amodiaquine granules were prepared by blending active ingredient with pregelatinized starch, sizing through appropriate sieves and granulation with maize starch paste in purified water high shear mixer.
  2. The wet mass was sized and dried at 600C to achieve the desired moisture content of the granules, determined by loss on drying. The dried were reduced by sizing through suitable sieves and suitable lubricated.
  3. Weight for outer amodiaquine tablet is 520.
Compression of Tablet in Tablet
The inner artesunate are compressed in a regular tablet press, then film coated. The tablet in tablet were produced on a specialized tablet press which operated by a specialized pressing procedure, whereby inner tablets are fed into the tablet in tablet press with amodiaquine granules and the press operated again such that a final product is of artesunate tablet inside amodiaquine.

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