Development of a Nanocrystal Formulation of a Low Melting Point API Following a Quality by Design Approach

Abstract

Preparation of nanocrystal formulations by wet media milling and spray-drying is a reliable technique to enhance dissolution and ameliorate absorption limitations of poorly soluble BCS II drugs. However, when thermosensitive compositions are dried at high temperatures, the risks of particle aggregation and thermal degradation must be considered. The present study investigates the effects of nanosuspension formulation variables when performing the spray drying process at equidistant temperatures above and below the melting point. Towards this purpose, Fenofibrate is exploited as a model drug of unfavorable pharmacokinetic profile and low melting point (79–82 °C), properties that render thermal processing a nontrivial task. Rationalizing the system’s behavior by combining molecular simulations with QbD methodology, the preparation of stable nanocrystals can be “steered” in order to avoid undesirable melting. The statistically resolved operational conditions showed that Fenofibrate Critical Quality Attribute–compliant nanosuspensions i.e., bearing hydrodynamic diameter and ζ-potential of 887 nm and −16.49 mV, respectively, were obtained by wet milling drug to Pharmacoat and mannitol weighted optimum ratios of 4.075% and 0.75%, after spray drying at the desired temperature of 77 °C. In conclusion, we present a quality assurance methodology of nano-comminution generally applicable for thermo-labile BCS II drugs.

Integrating Elastic Tensor and PC-SAFT Modeling with Systems-Based Pharma 4.0 Simulation, to Predict Process Operations and Product Specifications of Ternary Nanocrystalline Suspensions

“…By increasing the diameter after a specific value, a non-additional specific power input is needed to achieve the same result, and by decreasing the diameter of the mill after a specific threshold, no requirement of a specific power increase encumbers the same response. The operational area of the ball mill was validated between the specific values from our previous grinding Fenofibrate experimental results, delivering submicron crystals of characteristic (D50) size between 300 and 400 nm [16]. Given this and according to Figure 4, for the Aspen engine to simulate this level of grinding by using a D m = 10 cm mill diameter, an input-specific energy of E = 2600 kJ/kg or E = 702 kWh/ton is evidently required.…”

“…This paper refers to the experimentally validated global mechanistic study that bridges the aforementioned Pharma 4.0 enabling tools, to predict the processes parameters and their related product performance attributes, starting at the nanoscale level. Fenofibrate is utilized as a model drug, being a BCSII thermolabile API, well suited for solubility enhancement through WMD and SD processing [16].…”

Pharma 4.0 Continuous mRNA Drug Products Manufacturing

“…Taking into account the reaction's scalability limiting factor, we choose to incorporate three 10 L vessel reactor units. The RNA production rate response was statistically coded as quadratic and the relevant ANOVA [53] of results are demonstrated by Table 6. The projected F-value of 23.96 appoints significance to the model, hence only a 1.21% chance exists that the latter could be appointed to noise.…”

“…Purification of mRNA is performed by chromatographic steps AEX-301, AFC-301, and HPLC-301 and their related designed specifications are given by Table 7. [20,26,27,51,53,54]. Poly-A tails form the basis for binding in a poly (U)-Sepharose or a oligo (dT) -cellulose resin [31].…”

“…Purification of mRNA is performed by chromatographic steps AEX-301, AFC-301, and HPLC-301 and their related designed specifications are given by Table 7. [20,26,27,51,53,54].…”