Impurity profiling

Process validation should be extended to those steps determined to be critical to the quality and purity of the enantiopure drug. Establishing impurity profiles is an important aspect of process validation. One should consider chemical purity, enantiomeric excess by quantitative assays for impurity profiles, physical characteristics such as particle size, polymorphic forms, moisture and solvent content, and homogeneity. In principle, the SMB process validation should provide conclusive evidence that the levels of contaminants (chemical impurities, enantioenrichment of unwanted enantiomer) is reduced as processing proceeds during the purification process. 

H. Kramer, S. Semel J.E. Abel, Trace Elemental Survey Analysis of Trinitrotoluene , PATR 4767 (1975) (An evaluation of the applicability of spark source mass spectrometry and thermal neutron activation for the detn of origin-related trace elemental impurities in TNT) 10) C. Ribando J. Haber-man, Origin-Identification of Explosives Via Their Composite Impurity Profiles I. The... 

Ref C. Ribaudo J. Haberman, Origin— Identification of Explosives Via Their Composite Impurity Profiles, I, The Relation of the Origin of Military Grade TNT to its Mono-, Di-, and Trinitrotoluene Isomer Impurities , PATR 4768 (1975)... 

Changes to the synthesis or manufacture process that may affect the impurity profile... 

Figure 1.8. Schematic frequency distributions for some independent (reaction input or control) resp. dependent (reaction output) variables to show how non-Gaussian distributions can obtain for a large population of reactions (i.e., all batches of one product in 5 years), while approximate normal distributions are found for repeat measurements on one single batch. For example, the gray areas correspond to the process parameters for a given run, while the histograms give the distribution of repeat determinations on one (several) sample(s) from this run. Because of the huge costs associated with individual production batches, the number of data points measured under closely controlled conditions, i.e., validation runs, is miniscule. Distributions must be estimated from historical data, which typically suffers from ever-changing parameter combinations, such as reagent batches, operators, impurity profiles, etc.

Figure 4.8. Comparison of impurity profiles for the same chemical intermediate from two different suppliers. The impurity peak-areas for each chromatogram were tallied in 0.02 area-% bins for each vendor, the data was normalized by dividing by the number of chromatograms. Vendor A s material has many more peaks in the 0.05-0.2% range, which drives the total impurity level to =5.2% (vs. 1.9 for Vendor B) for <0.2% the number of excess peaks above 0.2% does not appear as dramatic, but greatly adds to the total impurity level = 13.3 v.v. = 2.3% ...

Figure 4.18. Peak-size correlation in an HPLC-chromatogram. The impurity profile of a chemical intermediate shown in the middle contains peaks that betray the presence of at least two reaction pathways. The strength of the correlation between peak areas is schematically indicated by the thickness of the horizontal lines below the chromatogram. The top panel gives the mean and standard deviation of some peak areas (n = 21) the two groups of peaks immediately before and after the main peak were integrated as peak groups.

An impurity profile that depends on precise experimental conditions. 

The crystallization step is generally studied quite exhaustively at the laboratory scale and often at the pilot scale. The reaction chemistry should be properly understood to access effects, if any, of the synthesis step on the impurity profile. In batch cooling crystallizers attempts have been made to create optimum conditions by on-line turbidity analysis (Moscosa-Santillan et al., 2000). Physicochemical characterization of the products should be done rigorously (Tanguy and Marchal, 1996). 

Crystalline materials are commonly associated with purity, but recent demands lead to almost suprapure materials, and it is common to ask for an impurity profile. Crystallization epitomizes purification at the molecular level and the technology exploits the ability of a crystal surface to reject molecules that it does not recognize (Davey, 1994). This is essentially a supramolecular process. Two types of approaches are possible, viz. the use of eutectic and solid solutions. In the eutectic approach there is efficient rejection, whereas in solid solutions molecular level discrimination is difficult. 

HPLC is extremely useful in monitoring and optimizing industrial processes. Conventional process monitors measure only bulk properties, such as the temperature and pressure of a reactor, while HPLC permits continuous realtime monitoring of consumption of starting materials, product composition, and impurity profile. There are a number of new initiatives relevant to HPLC for process monitoring, including sample preparation, automation, miniaturization, and specialized detectors. 

Since the final product is a pharmaceutical, high purity of the product is definitely required. Furthermore, the amount of any impurities in the final product has to be rigorously regulated under ICH guidelines. Rejection of impurities related to cyclopropylacetylene (37) was difficult throughout this whole process [28]. Thus, not only the isolated yield but the impurity profile of 37 was critical. 

The well documented synthetic method for 37 is chlorination of cyclopropyl-methylketone followed by base treatment [29]. However, this method did not provide a suitable impurity profile. The most convenient and suitable method we found was the one-step synthesis from 5-chloro-l-pentyne (49) by addition of 2equiv of base, as shown in Scheme 1.18 [21, 30]. Two major impurities, starting material 49 and reduced pentyne, had to be controlled below 0.2% each in the final bulk of 37, to ensure the final purity of Efavirenz . Acetylene 37 was isolated by distillation after standard work-up procedure. 

Scheme 8.14 Impurity profile in the coupling of N-Boc pyrrolidine with aryl bromide 3.

A combination of infrared spectroscopy with size exclusion chromatography has a wide application range in the characterization of copolymers, adhesives, impurity profiling in polymers and branching in polyolefines [60-65]. Commonly, the solvent used as a mobile phase absorbs strongly in the... 

The most common types of analyses are the identification test, the quantitative determination of active ingredients or major component, and the determination of impurities. The identification test provides data on the identity of the compound or compounds present in a sample. A negative result signifies that the concentration of the compound(s) in sample is below the DL of the analyte(s). The quantitative method for the major component provides data of the exact quantity of the major component (or active ingredients) in the sample, and a reported concentration of the major component must be higher than the QL. In a Determination of impurities test, one obtains data regarding the impurity profile of a sample, and can be divided into a limit test or quantitative reporting of impurities (see Table 1, which has been modified from Refs. [1] and [8]). 

A piperidene-based intermediate was found to crystallize as either an anhydrate or a hydrate, but the impurity profile of the crystallized solids differed substantially [26], Considerations of molecular packing led to the deduction that there was more void volume in the anhydrate crystal structure than in that of the hydrate form, thereby facilitating more clathration in the anhydrate than in the hydrate phase. This phenomenon was led to a decision to crystallize the hydrate form, since lower levels of the undesired impurity could be occluded and greater compound purity could be achieved in the crystallization step. 

Figure 9.3 shows an impurity separation under conventional pressures with a 5 /mi particle, 2.1 x 150 mm column, and the same separation performed via UPLC using a 2.1 x 50 mm column with 1.7 /im particles. The run time was improved by a factor of six, with overall resolution comparable to that of the original separation on the 5 /an column. The application of UHPLC technology to impurity profile analysis can exert a significant impact on laboratory productivity by achieving a... 

---