Volume 29(2) - Summer 2013

Solid drugs taken orally are mixtures of active pharmaceutical ingredients (hereinafter referred to as “API”); agents such as excipients added as binders or diluents; and lubricants added to enhance flow properties of particles. In general, active pharmaceutical ingredients are solid organic substances. In many cases, a substance of the same chemical formula can occur in several polymorphic forms with different crystal structures, a phenomenon known as crystal polymorphism. Compounds noted by the same chemical formula but having different crystal structures are known to exhibit different characteristics with regard to stability and bioavailability†. Conventional methods for distinguishing these polymorphs have been based on X-ray diffractometers and thermal analyzers.

Pharmaceutical development in recent years has begun to focus increasingly on stability, ease of administration (swallowing), and the efficacy of the final pharmaceutical production, in addition to the stability and bioavailability of the APIs. In response to the needs of an aging population, for example, development is currently underway in Japan on formulations that allow elderly people to swallow medications more easily. Companies have begun developing unique formulations (e.g., oral disintegrants, films, jellies) with added functionality and need methods to confirm not just the stability of the APIs, but also the stability of these functions. Reports indicate that more than 60% of new pharmaceuticals developed in recent years have low solubility, which has driven efforts to select the ideal additive to improve dissolution and/or to develop highly soluble amorphous formulations.

At the same time, the Japanese government has promoted the use of generic drugs to cut medical costs. In certain Western nations, market shares for generic drugs have reached 60–70%; in Japan, this share remains at 22.8% (statistics as of Sept. 2011 by number of products). Several measures including a revised remuneration system for medical care services have been taken to promote the use of generics. With the growing availability of drugs containing the same API from multiple manufacturers and increasing consumer choice, there is growing demand for ways to guarantee safety and quality and to set a product apart from the others.

In response, instruments used for analysis of these compounds have been modified in various ways and new methods of analysis have been developed. This special issue will focus on solid, orally administered formulations and present an overview of Rigaku’s analytical technologies that provide effective solutions to problems encountered from drug R&D to production. This issue also introduces the latest technologies in analysis.

In the early stages of new drug discovery, the structure of small molecule hits resulting from compound screening is modified to derive leads (putative drug molecules) and then the leads are optimized intensely to achieve a molecule with a higher affinity to the target protein. The atomic resolution protein structure indispensable to this optimization step is determined by X-ray crystallography. The structure of the lead itself including its absolute configuration is also important because optical isomers often have completely different effects on living organisms. Single crystal structure analysis is essentially the sole method for determining the absolute structure of a molecule.

The principle of single crystal analysis is quite simple and common in both small molecule and macromolecule crystallography. When a single crystal is irradiated with X-rays, they bounce off the electrons and interact to produce a set of diffraction spots, which researchers transform Fourier analysis to obtain the electron density inside the crystal. By assuming atoms reside at electron density peak positions, one can reconstruct the molecule. Experimental methods such as multiple isomorphous replacement method (MIR) provide phases necessary to calculate a Fourier transform in the case of macromolecule crystals. When a structure highly homologous to the target molecule is known, the phasing process becomes much simpler because the molecular replacement method can be used. This is the often the case with single crystal analysis as used in drug development.

The phenomenon whereby a single substance exhibits multiple different crystal structures is known as crystal polymorphism; the structures are known as polymorphic forms. Many active pharmaceutical ingredients (hereinafter referred to as “API”) of pharmaceutical drugs exhibit polymorphism. Differences in crystal type attributable to hydration may sometimes be referred to as pseudopolymorphism. Each crystal form is referred to as a polymorphic form.

In cases in which an API presents multiple polymorphic forms or pseudopolymorphic forms, the forms must be distinguished and controlled during the development and manufacture of pharmaceutical products, due to the potential for different solubilities and absorption rates. APIs can undergo phase transformations to other polymorphic forms or hydration/dehydration due to external factors such as temperature, humidity, pressure, exposure to light or by the addition of additives. This underscores the importance of assessing early in a research project what conditions may prompt phase transformations and which polymorphic forms may result.

Powder X-ray diffraction and differential scanning calorimetry (hereafter abbreviated, respectively, powder XRD and DSC) are fundamental techniques for distinguishing polymorphic forms in APIs. This paper will introduce methods for identifying crystal forms in active pharmaceutical ingredients using powder XRD and DSC, then present a method for examining the polymorphic forms of candidate compounds.

Many Japanese pharmaceutical companies are now intensively investigating methods for inspection of starting materials. One of the reasons is the PIC/S (Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme) accession of Japan in the near future. Since samples taken from all containers must be tested, speed of identification is strongly required.

Another requirement is the protection of the materials. There are contamination risks for opening the packages, and direct material identification through a glass bottle or a transparent bag is often required.

Handheld Raman spectrometers are recently recognized as an effective tool for starting material inspection. In the past, near infrared absorption spectroscopy was often used in this field. However, Raman spectroscopy, which supplies us much more information for samples, has a higher capability of material identification. The direct material identification through a glass bottle or a transparent bag is possible by Raman spectroscopy only.

Raman spectrometers used for pharmaceutical inspections must have performance characteristics described in USP <1120>. The portable Raman spectrometer reported here meets the requirements of USP <1120>.

The analysis of metal impurities for pharmaceutical products such as harmful elements contained in the raw materials and residual catalysts in the manufacturing process is important for the risk assessment in actual large scale production.

Various guidelines and criteria of harmful elements in pharmaceutical products have been established. According to USP?232? of the United States Pharmacopoeia (USP), pharmaceutical products are classified based on toxicity levels. The European medicines agency (EMA) has set guidelines for the limit of residual metal elements. Recently, the international conference on harmonization of technical requirements for registration of pharmaceuticals for human use (ICH) has proposed safety standard guidelines for metal impurities (Q3D) for the purpose of quality assurance of pharmaceutical products.

ICP-MS and ICP-OES have been typically used for the elemental analysis of impurities, but XRF analysis has been increasingly attracting attention due to the ease of sample preparation.

In this article, trace element analysis in pharmaceutical samples using an EDXRF (Energy- Dispersive X-ray fluorescence) spectrometer NEX CG that has superior sensitivity compared to conventional EDX spectrometers is introduced.

Data collection and processing have a significant impact on the structure analysis step. Considering the power of current direct method programs, quality data are nearly equal in importance to obtaining the initial structure when crystallographic difficulties such as an ambiguous space group and twining are not involved.

This article will describe problems and measures in obtaining diffraction data using two-dimensional detectors: a CCD and an IP detector.

For the expert small molecule crystallographer, where a flexible configuration is required, Rigaku offers the XtaLAB P200 chemical crystallography system. The XtaLAB P200 represents a state-of-the-art chemical crystallography system with its incorporation of the DECTRIS PILATUS 200K hybrid pixel array detector (HPAD). The XtaLAB P200 can be configured with molybdenum (Mo) radiation, copper (Cu) radiation, or a combination of the two. With a true photon counting detector, the XtaLaB P200 is the perfect choice of X-ray diffractometer for both day-to-day routine crystal structure determinations and the more challenging high-resolution electron density studies.

We have improved the conventional micro area stress measurement system (AutoMATE) by replacing the gas flowing detector Position Sensitive Proportional Counter (PSPC) with a semiconductor detector, the D/teX Ultra 1000. This new AutoMATE II provides the user with new functions, high sensitivity, high counting rate and good energy resolution. Maintenance of the AutoMATE II is much easier than that of AutoMATE because there is no longer the need to flow PR gas. The higher sensitivity of the D/teX Ultra 1000 enables the user to perform micro-area stress measurements in less time. The high counting rate capability of the D/teX Ultra 1000 means that the stress measurement of crystalline materials having coarse grains or textures can be performed easily.