Solubility formulation problems

For pharmaceutical formulations, the simplex method was used by Shek et al. [10] to search for an optimum capsule formula. This report also describes the necessary techniques of reflection, expansion, and contraction for the appropriate geometric figures. The same laboratories applied this method to study a solubility problem involving butoconazole nitrate in a multicomponent system [11],... 

The concentration of boric acid in the liquid detergent needed to obtain stabilization is typically around l-3%(w/w). Solubility limits prevents the use of concentrations of boric acid above a few per cent. The relatively high amount of used boric acid makes the detergent formulation more difficult to develop due to solubility problems and components being incompatible with high amounts of boric acid. 

The sample must be soluble If it s not in solution, it cannot be analyzed by HPLC. Although this may seem obvious, solubility issues complicate real assays of low-solubility drugs and controlled-release formulations. Many situations encountered in pharmaceutical analysis, such as low recovery, lack of mass balance, and out-of-specification results, might stem from solubility problems in a sample preparation step, rather than the HPLC analysis itself. 

Two interesting attempts to redesign these resist materials have been reported. The first consisted of altering the structure of the sensitizer such that it bleaches in the DUV (70). The resulting resist provided adequate sensitivity but suffered from sensitizer volatility and solubility problems and profile degradation was experienced in films over 0.5 jiim micron thickness due to the unbleachable absorbance of the matrix resin from which the resist was formulated. 

The third option is to incorporate API in a granulation liquid. This is also a preferred method for the manufacture of low-dose product. However, many APIs have a solubility problem in water. The application of a solvent for a granulation liquid involves the capability of the granulation system and causes some safety concerns. The selection of granulation method should consider the properties of the starting materials, formulation, product specification, the availability of equipment, and personal and equipment safety. 

The use of polyols such as pentaerythritol, mannitol, or sorbitol as classical char formers in intumescent formulations for thermoplastics is associated with migration and water solubility problems. Moreover, these additives are often not compatible with the polymeric matrix and the mechanical properties of the formulations are then very poor. Those problems can be solved (at least partially) by the synthesis of additives that concentrate the three intumescent FR elements in one material, as suggested by the pioneering work of Halpern.29 b-MAP (4) (melamine salt of 3,9-dihydroxy-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5,5]-undecane-3,9-dioxide) and Melabis (5) (melamine salt of bis(l-oxo-2,6,7-trioxa-l-phosphabicyclo[2.2.2]octan-4-ylmethanol)phosphate) were synthesized from pentaerythritol (2), melamine (3), and phosphoryl trichloride (1) (Figure 6.4). They were found to be more effective to fire retard PP than standard halogen-antimony FR. 

The primary reasons for the replacement of components are chemical instability, discoloration problems, problems of fragrance incompatibility with the product base (e.g., solubility problems), problems of incompatibility with the packaging, and demands of costing. The subsequent necessity to rebalance the formulation may also arise from several reasons ... 

Solubility problems in formulation Structure XVII Sulfamethoxazole, p/C = 6.03... 

Figure 5.14 summarises the physicochemical problems in the use of preservative molecules in formulations. Solubility and partition coefficients of ionised species are determined, as we have seen, by the pH and ionic strength of the system. In this example, partitioning may occur from the aqueous phase to the oily... 

The reason for the 250-ml cut-off criterion for the dose solubility ratio is that in pharmacokinetic bioequivaience studies, the API formulation is to be ingested with a large glass of water (8 ounces corresponds to about 250 ml). If the highest orally administered dose can be completely dissolved in this amount of water, independent of the physiological pH value (hence the determination over the pH range 1-7.5), solubility problems are not expected to hinder the uptake of the API in the small intestine. 

We formulate the problem in general terms first, and then consider several simplifying approximations in the subsequent subsections. Hence we begin by assuming that the surfactant may be soluble in both of the bulk fluids, that it adsorbs to and from the bulk fluids following Langmuir kinetics, and that the interfacial tension is related to the interface concentration of surfactant by means of the Langmuir limit of (2-155),... 

In summary, poor aqueous solubility is the single physicochemical property that is most likely to be problematical in a combinatorial library. It can be avoided in part by intelligent use of batch-mode solubility calculations. The solubility problem is not simply a technical issue in library design. It is exacerbated by chemistry synthesis considerations and by the timing of the availabihty of combinatorial exemplars. Formulation fixes are available unless the solubility is extremely poor, but these should be avoided as much as possible. Poor permeability is seldom a problem in combinatorial libraries, but is disastrous if present since effectively formulation fixes do not currently exist. 

Fosphenytoin sodium (Fig. 20.5) is a soluble pro-drug disodium phosphate ester of phenytoin (142 mg/mL) that was developed as a replacement for parenteral phenytoin sodium to circumvent the pH and solubility problems associated with parenteral phenytoin sodium formulations (36,37). Unlike phenytoin, fosphenytoin is freely soluble in aqueous solutions and is rapidly absorbed by the IM route. It is rapidly metabolized (conversion half-life, 8-15 minutes) to phenytoin by in vivo phosphatases. Therapeutic free (unbound) and total plasma phenytoin concentrations are consistently attained following IM or IV administration of fosphenytoin (26). It is administered IV following benzodiazepines for control of status epilepticus or whenever there is a need to rapidly achieve therapeutic plasma concentrations. Severe bradycardiac adverse events to fosphenytoin, including some fatalities, have been reported (38). A dose reduction in patients who are elderly or have renal or hepatic impairment has been suggested. 

Nanosuspensions consist of the pure poorly water-soluble drug without any matrix material suspended in dispersion. It is sub-micron colloidal dispersion of pure particles of drug stabilized by surfactants. By formulating nanosuspensions, problems associated with the delivery of poorly water-soluble drugs and poorly water-soluble and lipid-soluble drugs can be solved. Nanosuspensions differ from nanoparticles, " which are polymeric colloidal carriers of drugs (nanospheres and nanocapsules), and from solid-lipid nanoparticles, which are lipidic carriers of drug. 

One of the main problems with soluble (emulsifiable) oils is that they provide an excellent medium for the growth of microorganisms, requiring the addition of germicidal agents. It can therefore be seen that a fully formulated soluble (emulsifiable) oil is a highly complex mixture (Table 3). 

---