Method Of Manufacture Of Pyrazolo[3,4-b]Pyridine 271-73-8

1. To prepare the 4.5 pH Citrate Buffer solution: Dissolve Sodium Citrate in the minimum amount of water, heat if necessary to 50-60.degree. C. to aid dissolution. Dissolve the Citric Acid in the minimum amount of water, heat if necessary to 50-60.degree. C. to aid dissolution. Pour the Sodium Citrate and Citric Acid into a beaker and make up to 50% of the target mass of water required to make the bulk solution. 

2. Divide the Citrate Buffer solution from step 1 into two halves (pour equal quantities into two separate beakers). 

3. To one half of the prepared Citrate Buffer solution (prepared in step 1) add the N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyrid- in-5-yl]methyl}-4-({8-[(2-hydroxyethyl)(methyl)amino]octanoyl}amino)benzam- ide monohydrochloride micronized active drug substance, heat if necessary to 50-60.degree. C. to aid dissolution, and dissolve with the aid of a stirrer. 

4. In a separate beaker, add the Xylitol to approximately 20% of the target mass of water and mix until dissolved at 3000 rpm using a Silverson mixer. 

5. Add the Xanthan Gum to the Xylitol solution and mix at 3000 rpm until dissolved. 

6. Dissolve the Edetate Disodium Dihydrate (EDTA) in the minimum quantity of water. Heat to 50-60.degree. C. to aid dissolution if required and add to the bulk, mixing at 3000 rpm. 

7. Gradually add the remaining Citrate Buffer solution (prepared in step 1) to the Xylitol, Xanthan Gum, and EDTA solution. 

8. Gradually incorporate the N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]p- yridin-5-yl]methyl}-4-({8-[(2-hydroxyethyl)(methyl)amino]octanoyl}amino)be- nzamide monohydrochloride previously dissolved in the Citrate Buffer solution (prepared in step 3), to the solution (prepared in step 7) and mix for a further 3 mins. 

9. Dissolve the Potassium Sorbate in the minimum quantity of water and add to the bulk, and mix for a further 3 mins. 10. Add water to make up to the target mass solution and mix at 4200 rpm for 5 mins. 

This formulation is preferably be stored under a nitrogen headspace (and/or stored at about 5.degree. C.). 

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