Journal of Pharmaceutical and Biomedical Analysis 96 (2014) 68–76 Contents lists available at ScienceDirect Journal of Pharmaceutical and Biomedical Analysis j o ur nal ho me page: www.elsevier.com/lo cate/jpba Investigation of active pharmaceutical ingredient loss in pharmaceutical compounding of capsules Matthias D’Hondt a , Evelien Wynendaele a , Kirsten Vandercruyssen a , Tiene Bauters b , Johan Vandenbroucke b , Steven Mullens c , Chris Vervaet d , Jean Paul Remon d , Bart De Spiegeleer a,∗ a Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium b Department of Pharmacy, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium c Flemish Institute for Technological Research (VITO), Boeretang 200, B-2400 Mol, Belgium d Laboratory of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium a r t i c l e i n f o Article history: Received 12 February 2014 Received in revised form 12 March 2014 Accepted 14 March 2014 Available online 25 March 2014 Keywords: Pharmaceutical capsule compounding API loss Surface profilometry Radial distribution function (RDF) R-GETAWAY autocorrelation a b s t r a c t Pharmaceutical compounding of capsules is still an important corner stone in today’s health care. It allows for a more patient specific treatment plan as opposed to the “one size fits all”-approach, used by the pharmaceutical industry when producing fixed dose finished drug products. However, loss of active pharmaceutical ingredient (API) powder during pharmaceutical capsule compounding can lead to under-dosed finished drug products and annul the beneficiary therapeutic effects for the patient. The amount and location of API loss was experimentally determined during capsule compounding of five different preparations: 10 and 20 mg hydrocortisone capsules, 4 mg triamcinolone capsules and 0.25 mg dexamethasone capsules, using a 10% m/m self-made or commercial trituration. The total API amount present in the five capsule preparations varied between 90.8% and 96.6%, demonstrating that for certain preparations, significant API mass loss occurred during the pharmaceutical compounding of capsules. Swabbing results of the different compounding equipment and working areas indicated the mortar sur- face as the largest API loss location. An agate mortar accounted for the least amount of API loss, whereas an extensively used porcelain mortar accounted for the highest amount of API loss. Optical microscopy and roughness (R a ) determination by profilometry of the different mortar surfaces revealed a significant influence of the mortar surface wear and tear on the observed API loss. This observation can be explained by physical deformation, or scratch formation, of the relatively soft porcelain mortar surface, in which the API particles can become adsorbed. Furthermore, a small effect of the capsulation device material on the API loss was also observed. The presence of a chemical molecule effect on the API loss was demonstrated through data mining using a set of assay results containing 17 different molecules and 1922 assay values. The 17 median assay values were modeled in function of corresponding molecular descriptors, using stepwise multiple linear regression. The obtained MLR model, containing RDF060m, R6e + and R3m + variables, explained 92.5% of the observed variability between the 17 median assay values. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Capsules are in essence small containers which are filled with one or more active pharmaceutical ingredient(s) (API) and excipi- ents such as filling agents, flowing agents and solubilizing agents. These excipients need to be API-compatible, concerning chemi- cal stability, density, particle size and shape. Capsules are mostly ∗ Corresponding author. Tel.: +32 9 264 8100; fax: +32 9 264 8193. E-mail address: Bart.DeSpiegeleer@UGent.be (B. De Spiegeleer). gelatin-based, and were invented in the 19th century, primarily to mask the bad taste and unappetizing color of the active substances. It is a popular dosage form because of its stability, the high dosage accuracy, fast drug release and ease of swallowing. Today, the majority of all drug formulations are prepared industrially. The reasons for the popularity of industrially pro- duced medicines are the low costs, the high production speed, the complexity of the new drug formulations and the high qual- ity requirements [1–6]. A disadvantage of these industrial drug preparations is that this approach limits individualized medi- cation, resulting in a “one size fits all”-strategy. Alternatively, http://dx.doi.org/10.1016/j.jpba.2014.03.020 0731-7085/© 2014 Elsevier B.V. All rights reserved.