Chloramphenicol palmitate solubility

Tables 3 and 4 list thermodynamic values calculated for polymorphs of chloramphenicol palmitate and mefenamic acid, respectively. Absorption studies of chloramphenicol palmitate in humans show that suspensions containing polymorph B of chloramphenicol palmitate gave blood levels approximately 10 times higher than those produced by suspensions of polymorph A [49], This may be due to the significant (-774 cal/mol) free energy difference between the polymorphs resulting in a substantial difference in their solubility and dissolution behavior. This theory is supported by the almost identical blood levels due to polymorphs I and n of mefenamic acid, which have a small free energy difference (-231 cal/mol) and similar solubility and dissolution behavior (Table 4).

As in the case of chloramphenicol palmitate, it may be desirable to have the more soluble (less stable) polymorph of a drug. One method, based on thermo-... 

When drug polymorphs cannot interconvert as a result of being suspended in aqueous solution, a different bioavailability of the two forms usually results [126], For instance, the peak concentration of chloramphenicol in blood serum was found to be roughly proportional to the percentage of the B-polymorph of chloramphenicol palmitate present in a matrix of the A-polymorph [133]. The same concept has been found to apply to hydrate species, where the higher solubility and dissolution rate of the anhydrous phase relative to the trihydrate phase resulted in measurably higher blood levels when using the anhydrate as... 

Many drugs can exist in more than one crystalline form, for example chloramphenicol palmitate, cortisone acetate, tetracyclines and sulphathiazole, depending on the conditions (temperature, solvent, time) under which crystallization occurs. This property is referred to as polymorphism and each crystalline form is known as a polymorph. At a given temperature and pressure only one of the crystalline forms is stable and the others are known as metastable forms. A metastable polymorph usually exhibits a greater aqueous solubility and dissolution rate, and thus greater absorption, than the stable polymorph. 

Pancreatic enzyme activity may be low at birth, but enzymes such as amylase, lipase, and trypsin develop to adult levels within the first year of life. Premature infants appear to have lower amylase levels than do full-term infants. Low concentrations of pancreatic enzymes may be the reason why newborns have a decreased ability to cleave prodrug esters such as chloramphenicol palmitate. Lipid-soluble drugs may not be well absorbed by neonates because of low lipase concentrations and bile acid pool. ... 

A water-soluble formulation of chloramphenicol sodium succinate is available for i.v. use. Chloramphenicol succinate is hydrolyzed to chloramphenicol in the liver. Chloramphenicol palmitate is an insoluble ester suitable for p.o. administration. Chloramphenicol palmitate is hydrolyzed to chloramphenicol in the gastrointestinal tract. Chloramphenicol (generic and veterinary labeled) is also available in a variety of tablet and capsule strengths. A long-acting formulation of florfenicol is approved for i.m. and s.c. administration to cattle. This formulation contains three carriers... 

The possible effects of such modifications are of several kinds, some not directly concerned with therapeutic efficacy. In its new form the antibiotic may be more stable, more soluble, more palatable (chloramphenicol palmitate), better absorbed (erythromycin estolate), or less irritant to the tissues (polymyxin methane sulfonate). Some of the most far-reaching effects produced by a minor structural change are seen in demethylchlortetracycline, which, as compared with tetracycline, is more stable, antibacterially more active, and much more slowly excreted. 

At any one temperature and pressure, only one crystal (polymorph) form will be stable. Any other polymorph found under these condition is metastable and will eventually convert to the stable form, but the conversion may be very slow (sometime can take years). The metastable form is a higher energy form and usually has a lower melting point, greater solubility, and faster dissolution rate. Examples are chloramphenicol palmitate (Aguir etal. 1967) and sulfameter (Khalil et al. 1972). This sulfanilamide is reported to have six polymorphs. Crystalline form II is about twice as soluble as crystalline form III. Studies in normal subjects showed that the rate and extent of absorption is approximately 40% greater from form II. Table 8.3 provides a few examples of drugs that exhibit polymorphism. 

Thermal analysis has been used to identify and characterize polymorphs of chlordiazepoxide hydrochloride, phenobarbital monohydrate, chloramphenicol palmitate, 3 (3-hydroxy-3-methyl-butylamino)-5-methyl-as. triazino ZB,6-b7 indole (SKF 30097), sulfathiazole, and sulfanilamide-d4. Solubility vs. solvent composition diagroms have been useful in the systematic study of pseudopolymorphism in the antibiotics cephaloglycin and cephalexin. This technique is recommended for the detection of solvate farmation when the instability of the compound at elevated temperatures precludes the use of conventional thermal methods, or when poor crystal development limits the use of microscopic methods. 

In a third precipitation method, the fact that most substances are more soluble at a high than at a low temperature is to made use of. A saturated solution is made at a high temperature after which it is cooled until supersamration is achieved. This last method is the least suitable because in practice it is often difficult to cool rapidly. The chloramphenicol palmitate suspension as described in Table 18.19 is an example of a suspension prepared by precipitation. Chloramphenicol palmitate precipitates when the solution in a hot mixture of polysorbate 80 and propylene glycol is mixed with the cold aqueous gel. By vigorous stirring during the final step, small particles are obtained. 

Chloramphenicol 1 %, polysorbate 80 6 %, in water for injection has been suggested as an ophthalmic solution [95]. Other formulae have been given and some of these are collected in Table 6.10. A solution of the antibiotic has been prepared in 50% iV,iV-dimethylacetamide as an intravenous injection. N,N-dimethylacetamide is a hydrotropic substance, a group of compounds whose actions are discussed in Section 6.7. Different crystal forms of chloramphenicol palmitate are soluble to differing extents in solutions of polysorbate 60. A detailed study of the solubilization of chloramphenicol in cetomacrogol solutions has been reported by Rogers [98] Regdon-Kiss and Kedvessy [99] have studied the... 

The antibiotic is administered orally as the palmitate, which is tasteless this is hydrolysed to chloramphenicol in the gastrointestinal tract. The highly water-soluble chloramphenicol sodium succinate is used in the parenteral formulation, and thus acts as a pro-drug. 

In recent years, many parent drugs have been converted to esters to generate so-called prodrugs in order to overcome some undesirable property such as bitter taste, poor absorption, poor solubility, and irritation at site of injection. For example, antibiotics such as chloramphenicol [56-75-7] and clindamycin [18323-44-9] have been derivatized as their palmitate esters in order to minimize their bitter taste. 

Chloramphenicol prepared as its palmitate ester is an interesting study example with respect to polymorphism. This ester, synthesized to avoid the bitterness of the active moiety (see below), exists as four polymorphs, three crystalline forms and an amorphous one. Polymorphs A and B have been found in commercial preparations but only form B leads to satisfactory blood levels. This effect was first attributed to the lower solubility of the "inactive" form A (26), but it was later proved that the higher susceptibility of form B to esterases was, in fact, involved (27). 

Chloramphenicol (Fig. 8.24) is an antibacterial agent that is used topically to treat infections of the eye and ear, but systemic treatment is reserved for treatment of life-threatening diseases such as those caused by Haemophilus influenzae and typhoid fever. Systemic administration through oral or parenteral delivery poses several problems chloramphenicol has a very bitter taste that cannot be masked effectively by conventional flavouring agents, which means there are therefore formulation problems that are needed to overcome poor patient acceptance. Additionally, poor water solubility makes formulation as an aqueous solution for parenteral administration difficult. Formation of the palmitate ester renders the compound virtually tasteless, and, whilst it remains relatively insoluble in water, it can be formulated as an oral suspension to enable good patient acceptance. Enzymatic... 

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