Drug solubility inclusion

Some of the compounds previously discussed have been used in formulation studies with the eventual aim of enhancing the bioavailability and activity in vivo. The ferrocenyl compounds discussed here are quite hydrophobic, necessitating a drug delivery system. Compounds 4, 5, 7 and 36 were found to create 1 1 water soluble inclusion complexes with methylated (3 cyclodextrin (CD) after stirring overnight. Electrochemical experiments showed that, in methanol, they exhibited a weak interaction with the CD cavity, and that these interactions became stronger as the amount of added water increased, as expected. 

As mentioned in the introduction part (Subheading I.l), amphiphilic or lipophilic drugs can be encapsulated in the aqueous compartments of DRV in the form of soluble inclusion complexes with CD molecules. Thereby, a required initial step of this modified DRV technique is the formation of the CD-Drug inclusion complex. 

Cyclodextrins and their derivatives, which can form inclusion complexes with some drugs, have shown promising results in rabbit studies. Both drug solubility and/or ocular bioavailability are increased, and sometimes tolerability is improved. However, the properties of cyclodextrins in ophthalmic drug delivery are poorly understood, and their benefits are still to be proven in the clinic (Jarvinen et al. 1995). 

In aqueous solutions CDs are able to solubilize many hydrophobic drugs by taking up some lipophilic moiety of the drug into the cavity, through formation of water-soluble inclusion complexes [13]. Cyclodextrins can be found in just over 30 marketed drug products worldwide [58]. In aqueous solutions free drug and CD molecules are in dynamic equilibrium with the complexes and every complex unit is generally assumed to be free and independent of other complexes as well as of other excipients found in the solution. 

Thus, in a simplified and summarized view, A-type curves indicate the formation of soluble inclusion complexes. B-type suggests the formation of inclusion complexes with poor solubility. Bg-type response denotes complexes of limited solubility and a Bj-type curve indicates the formation of insoluble complexes. A-type curves are subdivided into AL-type (linear increase of drug solubility as a function of CD concentration), Ap-type (positively deviating isotherms), and A -type (negatively deviating isotherms) subtypes (Higuchi and Connors, 1965 Cabral-Marques, 2010). The complexation process is most frequently a 1 1 host/guest ratio however, 2 1, 1 2, 2 2, or even... 

Particle agglomeration is a common issue in RESS process. It becomes worse if residual cosolvent remains in the processed material. Several researchers have used various particle collection systems to overcome the agglomeration issues. Additionally, RESS process is only applicable to the compounds with good solubility in scCOa. Unfortunately, many poorly soluble compounds with high molecular weights and polar bonds are also poorly soluble in SCCO2 at moderate temperatures (less than 60 °C) and pressures (less than 300 bar). Cosolvents such as methanol can be added to carbon dioxide to enhance solubility of the drug. However, inclusion of solvent to... 

There are other soUd states which sometimes confuse the measurement and definition of solubiUty. The dmg may crystaUize as a hydrate, i.e. under inclusion of water molecules. If the hydrate form is more stable than the pure form it may be difficult to measure the intrinsic solubility of the drug at all. Often drugs tend to precipitate in an amorphous form, often under the inclusion of impurities. As with metastable polymorphs, such amorphous precipitates may lead to erroneously high solubility measurements. CommerciaUy, drugs are often crystallized in salt form, e.g. as the hydrochloride salt, a cation with a chloride anion. In these co-crystallized salts, a much lower solubility than the intrinsic solubility will typi-... 

PVA/p-CD/salicylic acid -p-CD forms inclusion complexes with different water soluble substances i.e. salicylic acid - The drug release from the PVA/p-CD gel is nearly proportional to time 235... 

Let us compare the methods applied by Pedersen for establishing the complex formation with a modern approach. Today tedious solubility studies are carried out almost exclusively with practical applications in mind, but they are not performed to prove the complex formation. For instance, one ofthe main reasons for the use of cyclodextrin complexes in the pharmaceutical industry is their solubilizing effect on drugs [8]. There, and almost only there, solubility studies are a must. As concerns spectroscopic methods, at present the NMR technique is one ofthe main tools enabling one to prove the formation of inclusion complex, carry out structural studies (for instance, making use of the NOE effect [9a]), determine the complex stability [9b, c] and mobility of its constituent parts [9d]. However, at the time when Pedersen performed his work, the NMR method was in the early stage of development, and thus inaccurate, and its results proved inconclusive. UV spectra retained their significance in supramolecular chemistry, whilst at present the IR method is used to prove the complex formation only in very special cases. 

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