The impact of low-level inorganic impurities on key physicochemical properties of paracetamol.

Trace inorganic impurities in active pharmaceutical ingredients (APIs) while having limited toxicological significance might affect the down stream processing properties of those substances. The level of impurities in paracetamol batches was quantified and mapped using inductively coupled polarization mass spectrometry (ICP-MS) and scanning electron microscopy coupled with energy dispersive X-ray microanalysis (SEM-EDX). The physical form of samples was assessed using X-ray powder diffraction (XRPD) and characterised thermally using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Surface properties were evaluated using inverse gas chromatography (IGC) and moisture sorption. Size distribution was measured using an aerosizer with dry powder dispersion. Physical analysis confirmed that the batches were of the same physical form and particle size distribution was shown to be similar. The SEM-EDX analysis however revealed the presence of aluminium on the surface of particles. This was supported by ICP-MS analysis, which showed different levels of aluminium between batches ranging from 0.1 to 5.6 ppm. IGC indicated that the batches with the highest aluminium content had the highest dispersive free energy. Differences in levels of inorganic impurities typically not considered significant in drug substance specifications correspond with differences in physical properties of APIs, with potential downstream consequences for processing and finished product performance.

[1]  G. Buckton,et al.  The Application of Near Infrared Spectroscopy and Dynamic Vapor Sorption to Quantify Low Amorphous Contents of Crystalline Lactose , 2004, Pharmaceutical Research.

[2]  J. Wolff,et al.  Sulfur-specific detection of impurities in cimetidine drug substance using liquid chromatography coupled to high resolution inductively coupled plasma mass spectrometry and electrospray mass spectrometry. , 2001, Analytical chemistry.

[3]  Peter York,et al.  The influence of pellet shape, size and distribution on capsule filling--a preliminary evaluation of three-dimensional computer simulation using a Monte-Carlo technique. , 2005, International journal of pharmaceutics.

[4]  R. Price,et al.  Influence of particle size and shape on flowability and compactibility of binary mixtures of paracetamol and microcrystalline cellulose. , 2004, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[5]  R. Forbes,et al.  Water vapor sorption studies on the physical stability of a series of spray-dried protein/sugar powders for inhalation. , 1998, Journal of pharmaceutical sciences.

[6]  Jerry Y. Y. Heng,et al.  The Effects of Milling on the Surface Properties of Form I Paracetamol Crystals , 2006, Pharmaceutical Research.

[7]  The changes in surface energetics with relative humidity of carbamazepine and paracetamol as measured by inverse gas chromatography. , 2001, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[8]  I. Grimsey,et al.  Properties of saccharides and saccharide derivatives in the dry and partially hydrated states , 2003 .

[9]  H. Frijlink,et al.  Air classifier technology (ACT) in dry powder inhalation. Part 2. The effect of lactose carrier surface properties on the drug-to-carrier interaction in adhesive mixtures for inhalation. , 2003, International journal of pharmaceutics.

[10]  P. York,et al.  Characterisation of the surface properties of α-lactose monohydrate with inverse gas chromatography, used to detect batch variation , 1996 .

[11]  S. Sartnurak,et al.  The impact of low levels of amorphous material (<5%) on the blending characteristics of a direct compression formulation. , 2002, International journal of pharmaceutics.

[12]  Hartwig Steckel,et al.  In vitro evaluation of dry powder inhalers II: influence of carrier particle size and concentration on in vitro deposition , 1997 .

[13]  T. Lundstedt,et al.  The Relationship Between the Dissolution Rate and the Particle Size of Prednimustine: A Disagreement with the Noyes-Whitney Equation , 1994 .

[14]  P. York,et al.  Characterisation of the surface energetics of milled dl-propranolol hydrochloride using inverse gas chromatography and molecular modelling , 1998 .

[15]  Graham Buckton,et al.  The use of gravimetric studies to assess the degree of crystallinity of predominantly crystalline powders , 1995 .

[16]  Interpretation of the differences in the surface energetics of two optical forms of mannitol by inverse gas chromatography and molecular modelling. , 1999, International journal of pharmaceutics.

[17]  I. Saracovan,et al.  Measurement of the surface energy of lubricated pharmaceutical powders by inverse gas chromatography. , 2006, International journal of pharmaceutics.