PHARMACEUTICALS

Figure 3 - API solubility increase in spray solvent using processing aids

also be made if the API ’ s solubility is increased significantly . It is not unusual for its solubility to be doubled , thus halving the amount of solvent required to dissolve a given quantity of API and also halving the time it takes to spray dry it . If a more significant solubility increase is required , the solution can be transiently heated above the solvent boiling point . In such a ‘ temperature shift ’ process , developed at Lonza ( Figure 2 ), a suspension of the API and polymer is made at room temperature , with the concentration of the API far in excess of room temperature solubility . The suspension is then fed under pressure and heated to above its boiling point for less than a minute using an in-line heat exchanger at the top of the spray dryer , causing it to dissolve . It is not unusual for this process to improve the solubility of the API by an order of magnitude at the elevated temperature compared to room temperature . To minimise the risk of drug degradation , the residence time in the heat exchanger is typically kept to less than a minute . This time is optimised for a specific product to minimise degradation while providing sufficient time for dissolution . Volatile processing aids can also be used to increase the solubility of ionisable API , usually in methanol . Either acetic acid or ammonia can be used , for basic or acidic API respectively . A molar excess

is added to the spray solution to increase solubility . Acetic acid has ‘ generally recognised as safe ’ ( GRAS ) status in the compendia and although ammonia is corrosive , the concentration required as a processing aid is sufficiently low that the safety and environmental risks are minimal . Both ammonia and acetic acid are sufficiently volatile that they will be removed during the spray drying itself , or during the subsequent secondary drying process . For example , the solubility of the API gefitinib in an 80:20 mixture of methanol and water is only about 0.5 wt %, which is at least several-fold lower than what would be ideal for efficient manufacture . By adding 2 wt % acetic acid , the solubility of the API is increased by more than tenfold to over 6 wt %. Similar success has been achieved with using ammonia for weakly acid API : the solubility of piroxicam in methanol is less than 0.25 wt %, but adding about 1 wt % ammonia increases this to more than 5 wt %. In both cases , the sustainability of the process has been increased dramatically by the clever use of a processing aid , which serves to both reduce the overall amount of organic solvent and reduce the hazard of the organic solvent used .

Outlook

Technology advances are already making a huge difference to the sustainability of the spray drying process . By enhancing the solubility of APIs in more benign solvents , the environmental impact of the process is greatly reduced , along with the hazards faced by operators in the plant . And more concentrated solutions reduce processing time and the associated energy consumption , another important factor in increasing the sustainability of the manufacture of medicines . •

J j

John Baumann

R & D DIRECTOR

LONZA SMALL MOLECULES john . baumann @ lonza . com www . lonza . com

24 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981