Compatibility studies

Since the 1969, when Jacobson and Rieir [83] demonstrated that the stability of penicillins with various tablet lubricants could be predicted from thermal analysis, many attempts have been made to use both DSC and DTA as the basis of compatibility prediction. The basis of the method is to blend the drug under investigation and the excipient at the 1 1 level and to scan through major 

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A recommended USAF guide in this connection is Ref 20. Compatibility studies with spacecraft materials are reported in Refs 23, 29 32... 

Addnl Refs (limited distribution) 1) G. Perrault, Polyesters Azotes. II Etude Prelimi-naire SurLa Fhrce De Mouillage , Rept No CARDE-TR-585/68, Valcartier (Can) (1968) 2) Apon, Report of Compatibility Study Between TNT/Aluminum and Polyester Resin , Contract MWDDEA-N-74-F-5642, Toulon (Fr) (1974) 3) A Chazal, Report of Compati-... 

The new phases were discovered by the combination of exploratory synthesis and a phase compatibility study. As commonly practised, the new studies were initially made through the chemical modification of a known phase. Inclusion of salt in some cases is incidental, and the formation of mixed-framework structures can be considered a result of phase segregation (for the lack of a better term) between chemically dissimilar covalent oxide lattices and space-filling, charge-compensating salts. Limited-phase compatibility studies were performed around the region where thermodynamically stable phases were discovered. Thus far, we have enjoyed much success in isolating new salt-inclusion solids via exploratory synthesis. 

Chemical compatibility studies with hydraulic conductivity tests must be performed over a long enough period of time to determine the full effects of the waste liquid. Termination criteria include equal inflow and outflow of liquid, steady hydraulic conductivity, and influent/effluent equilibrium. At least two pore volumes of liquid must be passed through the soil to flush out the soil water and bring the waste leachate into the soil in significant quantities. Reasonable equilibrations of the influent and effluent liquids occur when the pH values of the waste influent and effluent liquids are similar and the key organic and inorganic ions are at full concentrations in the effluent liquid. 

Crowley and Martini [48] reported on several studies evaluating the impact of unit process operations on hydrates. AU showed some level of dehydration liberating freed crystalline water to participate in moisture-mediated reactions. The authors speculated that such energetic processing conditions are likely to have a similar affect on hydrated excipients with a potential deleterious effect on moismre-sensitive APIs. They commented that classical excipient compatibility studies were ill-equipped to predict such moismre-mediated interactions and that compression, attrition and other energy-intensive unit operations were rarely mentioned as requiring investigations. 

Desai et al. [86] reported on the photolytic degradation of the anti-viral, sorivudine, which formed the inactive Z-isomer. On the basis of extensive dmg-excipient compatibility studies it was found that the incorporation of iron oxide pigments into the blends (direct compression or wet granulated) stabilised the dmg to photodegradation indeed, so much so that the tablet was found not to require a film coat. The data are summarised in Table 2.6. 

H. Leuenberger, W. Becher, A factorial design for compatibility studies in preformulation work, Pharm. Acta Helv., 50 (1975) 88-91. 

Many in the pharmaceutical industry, when they hear the term excipient interactions, think immediately of excipient compatibility studies. These studies are important in the development of new products, but as we shall discuss, they are only a small part of the overall scope of excipient interactions. The significance of excipient interactions can extend well beyond the development of the particular medicinal product. Excipient interactions can have implications for... 

Excipient compatibility studies are an important part of any preformulation screen for a new API. However, it is important to remember that an excipient compatibility screen can only indicate the excipients to be avoided because of an obvious chemical incompatibility. The results from excipient compatibility studies are not always easy to interpret, particularly if a physical interaction is found. As stated above, physical interactions can be detected using some form of calorimetry in conjunction with, e.g., chromatography, but the interpretation of the significance of the interaction probably requires prior experience of the excipient and its interactions. It is difficult to predict that the molecular structure of the excipient will interact physically with the chemical structure of the API molecule. 

Excipient compatibility studies are a form of preliminary stability assessment. It is important that they be executed appropriately. The precise details of the testing will probably be different for each organization carrying out such studies. However, certain general assumptions are implicit in this approach. The underlying principle is the Arrhenius relationship ... 

In simple terms, the reaction rate increases as the temperature increases. Broadly, the reaction rate doubles with a 10°C rise in temperature. The compatibility studies are intended to provide information quickly. Generally, the studies are carried out at elevated temperature, and the resultant mixture examined analytically to determine if a chemical interaction has taken place, or if a physical interaction occurred. 

There are two main approaches to excipient compatibility screening isothermal studies at an elevated temperature and variable temperature studies in which the temperature is steadily increased, as in DSC. Both approaches are valid, but it is important to note, as has been stated above, that excipient compatibility testing is not a definitive test. We cannot state that an interaction will not take place, even though one may not have been found. We can only state which excipients to avoid because there is a very obvious interaction. A typical scheme is given in Figure 1 for a DSC-based excipient compatibility study. (There are other schemes that are used successfully.)... 

The dibasic calcium phosphate dihydrate example discussed above is probably an extreme example of the instability of an excipient relating to the release of water. But many excipients exist in a hydrated state, and heating them for the purposes of compatibility studies, or accelerated stability testing, can cause any free water, and sometimes other types of water, to be released, which can then influence any potential interaction, or even interact itself with the drug. 

Botha SA, Lotter AP. Compatibility study between Naproxen and tablet excipients using differential scanning calorimetry. Drug Dev Ind Pharm 1990 16(4) 673-683. 

However, additional compatibility studies may be necessary to determine any potential incompatibilities between the excipients and/or API and the delivery device closure system. 

Aminabhavi, T. M., and H. G. Naik, Chemical compatibility study of geomembranes-sorption/desorption, diffusion and swelling phenomena , J. Hazardous Materials, 60, 175-203 (1998). 

Surfactant Selection Based on Drug-Surfactant Compatibility Study. 295... 

Aramwit, P, Kerdcharoen, T., and Qi, H. (200l8i) vitro plasma compatibility study of a nanosuspension formulation,PDA J. Pharm. Sci. Technol., 60 211-217. 

Formulation profile, which consists of physical and chemical characteristics required for the products, drug-excipient compatibility studies, and the effect of formulation on in vitro dissolution... 

Although solution state property and stability data are important, it is the data and characteristics of the solid state of the API that are of most value to the formulator. Therefore, it is recommended that further experimental information on the solid-state form of the API be gathered prior to initiation of the compatibility studies. Relevant solid-state parameters of the API that could be investigated for further information include (but are not limited to) ... 

Minimally, one should have a brief foreknowledge of the thermal and thermal/humidity solid-state stability of the API prior to initiation of excipient compatibility studies. These protocols should include investigation of stability at various temperature and humidity conditions and should always include information about both chemical stability and physical-form integrity of the API. Thermal and thermal moisture-induced solid-state chemical reactions are well known (5), with hydrolysis and oxidation being the most prevalent mechanisms of decay. Changes in physical form with thermal and... 

It is important to note that the overall purity of the material should be considered prior to investigation of excipient compatibility, such as starting impurity levels, levels of residual water content and residual solvents, as well as the presence and levels of heavy metal impurities. A consideration of the enantiomeric and diastereomeric purities of the materials should be given and may be correlated to instability noted in compatibility studies. 

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