Povidone and Crospovidone

There are a large number of publications on the good tolerance of polyvinylpyrrolidone [127-129,131,133-134,201,225]. A complete list with assessments is to be found in A Critical Review of tbe Kinetics and Toxicology of Polyvinylpyrrolidone by Robinson, Sullivan, Borzelleca and Schwartz,published in 1990 [225]. 

Because of the good tolerance of povidone, its Accepted Daily Intake (ADI) was adjusted to 0-50 mg/kg body weight by the FAO/WHO Joint Expert Committee for Food Additives (JECFA) in 1987 [372]. 

In 1983, the JECFA awarded crospovidone an ADI status of not specified , as on the basis of the available chemical, biochemical, toxicological and other data, the entire daily intake of the substance in the quantities to be expected did not represent any risk to health in the opinion of the JECFA. It therefore seemed unnecessary to set a numerical value for the ADI [215]. 

Many toxicological and biochemical studies have been carried out with the individual grades of povidone and crospovidone by the producers. They could be ordered there. 

There is also a published study on renal elimination after intravenous administration of povidone K12 and K17 in rats [97]. 

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Figure 35 Excipient-induced (povidone and crospovidone) oxidation of a tertiary amine (raloxifene hydrochloride).

Hartanuer KJ, Arbuthnot GN, Baertschi SW, Johnson RA, Luke WD, Pearson NG, Rickard EC, Tingle CA, Tsang PKS, Wiens RE. Influence of peroxide impurities in povidone and crospovidone on the stability of raloxifene hydrochloride in tablets identification and control of an oxidative degradation product. Pharm Dev Tech 2000 5(3) 303-310. 

A number of different grades of lactose are commercially available that vary in their physical properties and many studies have been reported in the literature comparing the behavior of these various materials in different formulations. A number of co-processed excipients which contain lactose are available for direct-compression applications co-processed lactose and starch (Starlac, Meggle/Roquette Freres), lactose and microcrystalline cellulose Microcelac, Meggle) lactose and cellulose powder (Cellactose, Meggle), lactose, povidone, and crospovidone (Ludipress, BASF). 

As the description of the nitrogen determination in the povidone (and crospovidone) monographs included in Ph.Eur. 5 and in USP26 is not exact enough to obtain always a complete degradation of the polyvinylpyrrolidone polymer a modified Ph.Eur. method is given here ... 

Furthermore Fig. 80 shows that povidone and crospovidone increase in a comparable way the dissolution of indomethacin forming the same complex between drug and polymer. As the particle size and the swelling of these two polmers is quite different, this could explain the slight difference of dissolution. 

Hartauer et al. [58] reported that peroxide residues in povidone (binder) and crospovidone (disintegrant) were attributable to the formation of the A-oxide oxidation product of raloxifene. The authors correlated residual levels of peroxide in the excipients with A-oxide formation and thereby gained understanding of the degradation mechanism. A radical-initiated oxidation mechanism would be expected to show a typical S -shaped autocatalytic curve, whereas these curves showed fickian kinetics that is, rapid initial formation of the A-oxide followed by a plateauing of the rate, with consumption of the peroxides, leading to a slowing of the reaction rate. 

Pantoprazole sodium was separately mixed in 1 1 ratios with sodium carbonate, mannitol, calcium stearate, colloidal anhydrous silica, povidone K90, crospovidone, and hydroxypropyl methylcellulose. The blends were stored at 40°C and 75% relative humidity, at 50°C and 75% relative humidity, and at 65°C for 30 days. No evidence for instability was noted, indicating that pantoprazole sodium is compatible with these common excipients. 

Ludipress —an excipient consisting of 93% alpha-lactose monohydrate, 3.5% povidone, and 3.5% crospovidone ... 

In systematic investigations into the dependence of complex formation on structure, no difference was found between soluble polyvinylpyrrolidone (povidone) and insoluble polyvinylpyrrolidone (crospovidone) for complexes with organic compounds [192]. 

With crospovidone, it is not possible to use the molecular weight or the K-val-ue as a means of identifying the different types, as is done with povidone, since crospovidone is completely insoluble and its molecular weight cannot be determined. Table 113 gives the product range available in the market. 

Agrylin Anagrelide HC1 0.5, 1 mg Capsule Thrombo-cythe-mia and myelo-pro-liferative disorders Inhibition of cAPM phosphodiesterase, ADP-collagen-induced platelet aggregation Anhydrous lactose, crospovidone, lactose monohydrate, magnesium stearate, MCC, povidone Shire... 

Crospovidone is compatible with most organic and inorganic pharmaceutical ingredients. When exposed to a high water level, crospovidone may form molecular adducts with some materials see Povidone. 

The most important and clearest means of identification is provided by the infrared spectrum. It is the same for all types of povidone. Figure 24 shows the infrared spectrum of povidone K 90, and Fig. 99 shows the infrared spectra of povidone K 30 (Section 4.3.1.1). The only disadvantage of this method of identification lies in the fact that crospovidone gives the same spectrum (see Section 3.3.1.1). However, the difference can readily be determined from the solubility. 

Figure 55 shows the influence of an addition povidone K 90 on the sedimentation behaviour of micronized crospovidone in water at different concentrations. A 7.5% suspension of micronized crospovidone to which 5% povidone K 90 had been added showed no sedimentation within 24 hours, and its redispersibility was very good. Without povidone, significant amounts of crospovidone settled out. 

The designation polyvinylpolypyrrolidone (PVPP) is still used in the literature, although it is certainly not correct. This is confirmed by a comparison of the infrared spectra for crospovidone and povidone, which reveals no recognizable difference (see Section 3.3.1.1). 

As with povidone, crospovidone also forms chemical complexes or associates with a large number of drugs and other substances. For a typical example of comparison see Section 3.4.3.1. Here, too, the formation of the complexes is reversible and they do not form in alkaline medium. Whether crospovidone forms a complex with a drug depends on its chemical structure. 

The tests for hydrazine and 2-pyrrolidone, which are specified by the Pharmacopoeias for povidone, are not required for crospovidone, as these impurities are not present. Also residual solvents or organic volatile impurities are not present. 

As described in Section 3.4.2, crospovidone can contribute to improving the dissolution and bioavailability of a drug, as a result of its disintegrating properties. However, these properties are inadequate for a number of drug substances, as their solubility in gastric juice is poor. In such cases it is worth considering complexing them with crospovidone in the same manner as with povidone (see Section 3.2.5.1). 

All the active substances investigated so far were converted to the amorphous form by trituration with crospovidone, and this always remained stable in the few trials that have been conducted so far (Table 140). Stability results are available for a much larger number of drugs in coevaporates with crospovidone (Table 141). As all the drugs tested in coevaporates were found to have very good physical stability of their amorphous state, the same can be assumed for triturations. This correlates with similar results obtained with povidone (see Section 2.4.3.2). 

In principle, an improvement in the dissolution rate and bioavailability of all the drugs, whose dissolution and bioavailability can be accelerated with povidone (Section 2.4.3) can also be expected if they are coevaporated or triturated with crospovidone. This may be expected, as the effect of increasing the surface area by... 

The stabilized vitamins are sensitive against hydrolisis and chemical interactions with other vitamins. Similar to povidone [569] the stabilization effect of crospovidone could be described as desiccant action. 

An auxiliary such as povidone, crospovidone or copovidone cannot be registered as such by the authorities for use in pharmaceutical products. In Europe, Japan or America, it is always only possible to register a finished drug. There is no general positive or negative list of auxiliaries used in pharmaceuticals. It is only possible to state in which countries pharmaceuticals that contain povidone, copovidone and/or crospovidone are registered. 

In practice, a pharmaceutical preparation that contains povidone, copovidone and/or crospovidone can only be registered if these auxiliaries meet the requirements of the monographs in the pharmacopoeias that are regarded as mandatory in the countries concerned. The products described in this book meet these requirements (Table 183). 

Pharmaceutical products that contain povidone, crospovidone or copovidone have been registered in all important drug markets like Europa, USA, Japan etc. for parenteral, oral and topical administration. 

Drug Masters Files are only required for the registration of excipients not included in the Pharmacopoeias as monographs. Therefore for povidone, crospovidone and copovidone a DMF is not needed for the registration of a drug containing one of these excipients. 

In 1987 the World Health Organization (WHO + FAO) specified an Accepted Daily Intake (ADI) value for soluble polyvinylpyrrolidone (povidone) in food of 0-50 mg/kg body weight [372]. For Crospovidone the ADI value is not specified and therefore no limit is given for the application in foods [215]. 

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