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Regret for the inconvenience: we are taking measures to prevent fraudulent form submissions by extractors and page crawlers. Received: April 22, Published: May 10, J Anal Pharm Res 2 3 : DOI: Download PDF. The aim of this study was to investigate the peroxide free instant release polymer in the instant release matrix tablet and examine the oxidative degradation of raloxifene when used as a wet binder. Binders are important ingredients of solid oral dosage formulations SODFs.
The stability of active ingredients depends on external factors, e. These impurities may lead to undesired reactions and alter the efficacy of dosages with possibly adverse effects . Thus, controlling these impurities is important in alleviating the degradants to enhance the shelf life of drug products. Peroxides, amongst many of the impurities, remain the most challenging in drug development.
For instance, wet granulation though remains widely practiced in the industry for its simplicity and easy scale up, can exert an enormous mechanical stress on the excipients caused by multiple formulation steps involving blending, mixing, granulation, drying, and sieving . Such processing steps can lead to elevated impurity levels.
Thus, minimizing the risks for elevated impurities in the excipients, especially the peroxides, is highly essential, which could otherwise be detrimental to long term stability of pharmaceutical dosages [5 6]. Oxidative degradation has been studied extensively .
In a matrix dosage wherein the drugs and excipients typically are intimately in contact, an elevated level of peroxide may lead to significant oxidation of sensitive drugs, especially those bearing tertiary amines and secondary alcohols. Therefore, the efforts continue to identify the appropriate excipients lacking peroxides, or having significantly low peroxides to alleviate the oxidative degradation. PEG-PVA, developed first as an instant release coating polymer for immediate release coatings, has also been used as a hydrophilic pore former in the drug layering for sustained release tablets .
Raloxifene, bearing a tertiary amine and being highly sensitive to oxidation, has been investigated to demonstrate the feasibility of PEG-PVA as an alternative binder to control oxidative degradation to N-oxide, and perhaps other sensitive drugs alike. Unless noted otherwise, the statistical analysis was not performed as all the data points were a single measurement on each individual samples.
In addition, PEG covalently bound to polyvinyl alcohol acts as an internal plasticizer and provides a high flexibility, thus allowing the polymer to overcome the mechanical stress during manufacturing and storage of dosage forms.
Tablet properties such as tablet weight, thickness, hardness, friability, and disintegration time with PEG-PVA and povidoneK30 were evaluated and found to be comparable with both binders with the individual corresponding amounts used. Granule properties such as particle size and compression profile were evaluated, and compared with copovidone and HMPC granules.
The hardness of the granules, increased as a function of compression forces in both fluid bed and high shear granulations. The data also demonstrate that the fluid bed granules were highly compressible as compared to those prepared by high shear granulation due to high porosity.
In the high shear mixing, the granules however were densely packed, less porous, and hence were less compressible. Taken collectively, the data suggest that PEG-PVA exceptionally performed as a wet binder in fluid bed and high shear granulations, and the compression profiles of resulting granules were similar to those obtained with copovidone, HPMC and povidone K The oxidative degradation of raloxifene to N-oxide is shown in Figure 3.
The stability data, as shown in Table 5, suggests that raloxifene tablets with PEG-PVA were stable over 6 month period without degradation. Likewise, the tablets with povidone K30 bearing the low peroxide e. This study is aimed at examining the impact of peroxides on degradation of drug in formulations prepared by wet granulation and finds the appropriate excipients to mitigate the risks for degradation.
Those residual peroxides typically originate during the manufacturing process and get carried over practically in many of the excipients used in formulation. These peroxides not only limited to binders and disintegrants such as povidone and crospovidone but to other ingredients such as fillers, lubricants and surfactants, can also cause oxidative degradation of sensitive drugs. Hartauer et al. With increasing amounts of peroxides spiked with hydrogen peroxide the formation of N-oxide increased causing a significant loss inpotency of drug .
In a subsequent investigation, Yarkala et al. A further study suggests that the formation of N-oxide was not limited to formulation only but was also observed in the synthesis of raloxifene .
Oxidative degradation of raloxifene may lead to adverse reactions . Our data demonstrates that the PEG-PVA as a peroxide-free binder can withstand the robust processing conditions and can minimize the risk of oxidative degradation as evident from the data in Table 5. Controlling the residual peroxides is therefore critical to improve long term stability and to maintain the quality of pharmaceutical dosage forms, and the research continues to find the optimal solutions.
The possibilities include the use of antioxidants or smart packaging to alleviate the oxidative degradation [19,20]. The data from this study demonstrates that PEG-PVA, lacking the inherent residual peroxides as shown in Table 4, curtails the oxidative degradation of raloxifene in the tablets.
Taken collectively, this study also demonstrates that PEG-PVA was exceptionally stable and did not show a peroxide increase under the various ambient stability conditions over a 5 years period. The stability data reveal that the peroxide level does not increase at ambient and accelerated stability conditions. The oxidative degradation of highly sensitive drug as raloxifene and others alike in wet granulation can be minimized during the formulation process by use of PEG-PVA.
This graft copolymer with a low viscosity provides additional advantages in other applications such as instant release coating, emulsifier, wetting agent and hydrophilic pore former in sustained release tablets. This study also provides an understanding on controlling the degradation of raloxifene and other drugs alike highly sensitive to peroxides by selecting the appropriate binders or excipients lacking residual peroxides.
Thus, PEG-PVA with remarkable properties as binder and coating polymer, and free of peroxides, brings a new generation of excipient that could be widely applied to a range of wet granulation formulation development of highly sensitive drugs prone to oxidative degradation.
This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and build upon your work non-commercially. Withdrawal Policies Publication Ethics. Journal of. Research Article Volume 2 Issue 3. Go to Figure 2: Compression profiles of ascorbic acid tablets prepared from the granules prepared by fluid bed and high shear granulations; the compressions were carried out on each individual samples, hence no statistical data.
Stability condition 3 mo. Figure 3: Oxidative degradation of raloxifene. Tweets by medcraveonline.
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