ASSESSMENT OF THE IMPACT OF HUMIDITY ON STABILITY OF APOTRIAVIR TABLETS AND ITS IMPLICATION IN BETTER TASTE RELEASE TRACPlus 2010 KIGALI, November 11, 2010

I. Background Beginning of 2009, especially in March 2009 Reported from ARVs delivering sites : bitterness of APO-TriAvir Physical integrity of APO-TriAvir tablets (easily breakable) Nearly instant disintegration of the dosage form in contact with saliva.

Background (cnt’d) Friability was conducted and the results show that it is in acceptable range (between 0.0045% and 0.74% of weight in loss). Small survey at TRAC Clinic: 71% of patients preferred to take Duovir-N brand than APO-TriAvir According to 75% patients APO-TriAvir tablet dissolves immediately About 8% missed their doses in 3 weeks before survey due to Apo- TriAvir bitterness.

Tablet composition APO-TriAvir: PA Zidovudine 300mg Lamivudine 150mg Nevirapine 200mg Non active ingredients: Microcrystalline cellulose Methylcellulose Croscarmellose Sodium Magnesium stearate Colloidal silicon dioxide 4

Why instant disintegration ? Why bitterness ? Hypotheses: Composition Storage conditions (environment humidity) Combination of the two factors Stability studies under different percentage of Relative Humidity 5

II. Material and methods SAMPLE CHARACTERISTICS Brand name: Apo-TriAvir Date of fabrication: June2006 Manufacturer:APOTEX,Toronto, Canada Expiration date:2011August TESTING METHODS Visual inspection Uniformity of mass Friability test Disintegration test Stability test 6

Disintegration apparatus Friability machine Disintegration apparatus 20 intact tablets weighed (w1) Operate friability machine for 30 minutes at a rotating speed of 25 rpm Tablets removed, dedusted and weighed (w2). One tablet was placed in each of the six tubes and a disk was added to each tube. Operate for 15 minutes using water as the immersion fluid at a temperature of 37 ± 2 °C Record complete disintegration time F = 7

Stability testing MgCl2 (33% RH), NaCl (75% RH) K2SO4( 97% RH) 8

III. Findings and discussions Visual inspection At low humidity level (MgCl2, 33%) tablets were white with yellowish points, they were roughly consistence, fine shaped with the presence of letters (XCL and APO-TriAvir) on both sides; At relatively higher humidity (NaCl 75%) yellowish color more pronounced, XCL and APO- TriAvir still visible, shape was still fine but tablets were more friable; At higher relative humidity (K2SO4, 97%), tablets somehow brown, XCL and APO-TriAvir completely absent, shape lost, extremely friable, some broken

Weight gain The average mass of a tablet before stability testing was 883 mg mean weight/tablet are represented in the table bellow upon 1 month stability testing Relationship: weight gain  water absorption water absorbed  friability

Mean time of disintegration Disintegration time RH Tablets MgCl2: RH=33% NaCl: RH=75% K2SO4: RH=97% 1 9 min11 sec 7 min 18sec 1min 50sec 2 9 min9 sec 7 min 20sec 3 9 min10 sec 4 7 min 22sec 5 6 Mean time of disintegration Dis time before stability testing: 10 min Disintegration  drug dissolution Aggregates then fine particles  Fine particles in the bottom of the beaker 

Disintegration Dissolution  Bitter taste release The fast disintegration leads to a big amount of active ingredients in saliva directily in contact with tongue sensors  Early appearance of the bitterness and its intensity depending on how much drug has been dissolved in the mouth; The short disintegration time is beneficial for fast active ingredients availability, but might be responsible of poor compliance due to the bitterness; Bitterness associated to AZT APO-TriAvir tablets may not withstand higher relative humidity prevailing in tropics 12

Conclusion and recommandations TRACPlus To explain to patients that bitter taste is linked to drug properties and request them not to leave flasks open or to repack their drugs in papers and travel with, because this practice may contribute to the fast appearance of bitter taste. Request them to report any unusual taste feeling and get advices than missing doses. MANUFACTURER (APOTEX) Equilibrium and/or choice of binders and disintegrating agents would be advised in order to optimize stability of tablets in regions with higher relative humidity This can also delay a bit the onset of drug release and therefore, the apparition of the bitter taste. Although impacting on the cost, the coating of bitter drug before combination can be an option.

Thank you all !!