In the Pharmaceutical Industry powder mixing, being dry (or wet) mixing excipients with active pharmaceutical ingredients (API), is key to ensure the safety (right drug dose) in a tablet or dry powder inhaler. Two industry developments further increase the need for solid mixing techniques. First, the increasing potency of new API’s results in lower and lower dosed formulations to be developed, and second the Pharma 4.0 initiative is driving companies to move from batch to continuous processing (incl. mixing).
In the industry mixing occurs in small scale batch processes up to around 50 kg for dry powder inhalers and up to around 1000 kg in formulations for tablets. Typically two approaches of mixing occur, being: 1) random mixtures where API and Excipients are matched to reduce the chance of segregation during and after blending on stability and further processing; and, 2) adhesive or ordered mixtures in which the API is milled or micronized to sub 10-50 micron particles and which are combined with large, dense good flowing excipients. In the latter approach, the binding force is cohesion and in particular the Van der Waals forces, which avoid the segregation potential of a mixture.
In this study we focus on the mixing challenges related to the two mentioned developments in the pharmaceutical industry: (a) very low dose API mixing for direct compression and the effect of excipient morphology on the content uniformity and powder behavior and (b) moving from batch to continuous processing (mixing) . In both studies, both adhesive and ordered mixtures have been made by using simple mixing procedures.
To understand the role of excipient morphology on very low dose direct compression (DC) formulations we investigated formulations having a dose between 0.5 and 0.005%w/w API. These formulations were made with a range of (large) lactose-based excipients with different surface morphologies. The API size was calculated as per Rohr et al., 2006, to have enough particles present to enable a good content uniformity. Samples were taken both after the mixing process of the powder blend, as well as after tableting. This enabled us to analyze content uniformity of the blend versus content uniformity in the tablet. In addition, it enabled us to assess the level of segregation during holding time and potential segregation during the tableting process (RoTab).
To understand the differences in content uniformity (and behavior) batch mixing (Turbula mixer) was compared with continuous mixing (Gericke continuous mixer) with a fixed API dose. Samples of the powder blend were taken at different mixing time points and were analyzed. In addition, tablets were made from both blends to investigate the impact of both mixing processes on the tableting process and the resulting tablets. Clear differences in content uniformity and powder behavior were observed between both processes.
In both case studies it was concluded that in order to obtain non-segregated homogeneous powder blends and end products, the correct excipient (morphology) should be selected for the API size and the mixing process of choice.. These conclusions are applicable to powder mixing for oral solid dose applications (e.g. tablets) as well as dry powder inhalers.
Dr Bastiaan Dickhoff joined the T&I department team at DFE Pharma in 2014 in the capacity of Application Specialist OSD. Bastiaan has been working on assisting in application development of excipients in area of Oral Solid Dose Forms based upon fundamental knowledge of DFE Pharma’s excipients and advances in powder technology. His expertise lies in the understanding powder behavior in batch and continuous processes coupled with multivariat analysis. In addition, he is from a Technology and Innovation point of view responsible for the outcome of external collaborations. Prior to working at DFE Pharma Bastiaan held two (2) roles concerning the effect of powders in food and pharma at RSSL (which is part for Mondelez International (UK)) and prior to that Bastiaan has worked between 2005-2012 for GlaxoSmithKline (UK) in various roles.
Bastiaan holds a PhD from the department Pharmaceutical Technology and Biopharmacy at Groningen University, The Netherlands where he specialized in the relationship between the role of lactose (excipient) and API for inhalation purposes.