Residual solvents class

All crospovidone grades meet the ICH requirements on residual solvents according to Ph.Eur., 5.4 No residual solvents (class 1-3) are likely to be present. Furthermore they meat the requirements for organic volatile impurities of USP 26. 

Lamination Inks. This class of ink is a specialized group. In addition to conforming to the constraints described for flexo and gravure inks, these inks must not interfere with the bond formed when two or more films, eg, polypropylene and polyethylene, are joined with the use of an adhesive in order to obtain a stmcture that provides resistance properties not found in a single film. Laminations are commonly used for food applications such as candy and food wrappers. Resins used to make this type of ink caimot, therefore, exhibit any tendency to retain solvent vapor after the print has dried. Residual solvent would contaminate the packaged product making the product unsalable. 

MJ Thompson, RA Goldstein. Predicting solvent accessibility Higher accuracy using Bayesian statistics and optimized residue substitution classes. Proteins Struct Funct Genet 25 38-47, 1996. 

Solvent Effects in the Sn Spectra of Poly(TBTM/MMA). Samples of poly(MMA/TBTM) synthesized by the free-radical copolymerization of the appropriate monomers were solutions in benzene with approximately 33% solids (weight to volume). The particular formulation chosen as representative of the class contained a 1 1 ratio of pendant methyl to tri-n-butyltin groups. In preparing the dry polymer, the benzene was removed in vacuo with nominally 5% by weight residual solvent. 

Residual solvents are the third general classification of impurities in pharmaceuticals. This class is described as inorganic or organic liquids used during the manufacturing process. Typically, these solvents can only be evaluated by gas chromatography and therefore will not be addressed in this chapter. 

GC is most commonly used to determine residual solvents since these compounds are volatile. For example. Figure 1.6 [15] illustrates the use of GC to measure ICH Class 2 solvents. The solvents are dissolved in DMF and heated at 80°C for 60 min, and a sample of the headspace is injected into a capillary GC system fitted with a flame ionization detector. 

Residual solvents are divided into three classes. Class 1 solvents are those known to cause toxic effects and should be avoided in the production of active substances and excipients. Class 2 solvents present less severe toxicity than class 1, and class 3 solvents have such low toxic potential that exposure limits are not necessary. Table 12 presents the general characteristics of the solvents included in each class, and Table 13 lists the solvents and their concentration limit in pharmaceutical products. 

The long-term stability of an oral liquid formulation can also be affected by a number of unexpected reasons. Contamination by solvents used during the tank cleaning or even in the manufacture of excipients or API can be a source of instability of an oral solution. Uncontrolled levels of Class I, II, or III solvents could lead to the rejection of a batch or an excipient vendor. Class III solvents have a permitted daily exposure of 50 mg or less per day. (See the International Conferences on Harmonization, Impurities Guidelines for Residual Solvents. Q3C, Federal Register 1997 62(247) 67377 and also http //www.fda.gov/cvm/Guidance/guidelOO.PDF). 

List taken from International Conference on Harmonization (ICH), harmonized tripartite (Europe, Japan, United States) guideline entitled Impurities Guideline for Residual Solvents. The above solvents are categorized as Class 3 solvents, with low toxic potential to man. Class 3 solvents have permitted daily exposures (PDEs) of 50 mg or more per day. 

Solvents other than the above Class 3 or Class 2 solvents may be used, but doing so requires that the user provide information to assure regulatory agencies that there will be no untoward health consequences from the level of their presence in an API. Clearly, PDE information showing that the drug product containing the expected level of residual solvent was safe would be best. 

Class 3 Residual Solvents with Low Toxic Potential (PDE) ... 

Solvent residues are impurities that are hard to completely remove during the technological process. This brings the necessity to determine their levels in the final product. According to ICH standards, residues of Class I have to be always identified and quantified. Similar procedures concern the residues of Class II and III if the concentration levels exceed acceptable norms [9]. 

Excipient impurity profiles and how to evaluate this important aspect of excipient manufacture, particularly in light of the International Conference on Harmonization (ICH) guidance published in 1999, also are addressed. Care must also be taken that residual solvent levels do not exceed those prescribed in the ICH Guidance for Residual Solvents published in 1999. Solvents are divided into three classes ... 

The level of Class 1 residual solvents should be strictly controlled below the concentration limits for every individual solvent (for example the limit for benzene is 2 ppm). Class 2 solvents are controlled according to the permitted daily exposures (PDFs) and maximum daily dose (Option 1 and Option 2). ICH Q3C provides PDFs for all Class 2 solvents. For Class 3 Solvents, ICH Q3C suggests that a PDF of 50mg/day or less would be acceptable without justification. For solvents for which no adequate toxicological data are found, manufacturers should supply justification for residual levels of these solvents in pharmaceutical products. 

ICH Q3C guides in determining, on a safety basis, acceptable residual solvent levels for intake by use of the term permitted daily exposure (PDE). This Guidance classifies residual solvents used in the synthesis and processing into four categories. The Guidance recommends that Class I solvents be avoided. These include benzene, carbon tetrachloride, 1,2-dichloromethane, 1,1-dichloroethane, and 1,1,1-trichloroethane. Table 2 is an example from the list of Class II solvents that should be limited because of their inherent toxicity either by calculation of concentration (PPM) or by PDE. 

An additional broad area of utilization of GC is the determination of residual solvents (organic volatile impurities). The solvents allowed for use in the synthesis and manufacture and their respective residual limits have been addressed by the ICH. Tests for residual solvents should be conducted whenever production or purification processes may result in the presence of such solvents. This mandates that residual solvents be determined in drug substances. For drug products, residual solvent levels may be calculated from the levels in the ingredients used to produce the drug product unless class 1 (to be avoided) or class 2 (to be limited) solvents are used in the manufacture of the drug substance, excipients, or drug product. ... 

Conducting polymers like commercially available PEDOT PSS are the third class of printable conductors. However, their conductivity (maximum 500 S/ cm for PEDOT PSS [11]) is several orders of magnitude lower than the conductivity of metals. The advantages of PEDOT PSS are its transparency, flexibility and low-temperature post-processing the thermal treatment is only necessary to remove residual solvent, no sintering is required. 

The phenomenon whereby solvent or water is incorporated in the crystal lattice or in interstitial voids, for example, has been termed pseudopolymorphism. When incorporated into a crystal lattice, the solvent usually has a space-filling role, especially where solvent molecules do not show strong interactions. If the crystal has large empty channels or holes, their nature will determine which solvent will be included and the structure of the resulting solvate. Although solvates can show higher solubilities and dissolution rates compared to non-solvated species (e.g., Stoltz et al. 1988 Suleiman and Najib 1989), solvates cannot normally be used in the pharmaceutical arena. Residual solvents have been classified the ICH into three classes ... 

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