Dorzolamide hydrochloride

These constants are similar to those reported for the structurally similar carbonic anhydrase inhibitor, dorzolamide hydrochloride, (6.4 and 8.2,... 

Dorzolamide hydrochloride is a white to off-white crystalline solid. 

Orally administered carbonic anhydrase inhibitors lower the intraocular pressure of glaucoma patients, however they induce a number of intolerable side effects associated with extraocular inhibition of the enzyme [5,6]. Thus, much research has been directed towards the search for a topically effective agent. Several compounds have been synthesized since the 1980 s in Merck Sharp Dohme Research Laboratories, and have been found to be topically active in man [7]. Unfortunately, many of these compounds were not very soluble. Attempts to obtain an active carbonic anhydrase inhibitor with good solubility resulted in the synthesis of Dorzolamide hydrochloride [8,9], which was first made available for pharmacological evaluation in 1987. Like other carbonic anhydrase inhibitors sulfonamides (such as acetazolamide, ethoxzolaniide, and methazolamide) dorzolamide is an inhibitor of human carbonic anhydrase isoenzymes I, II, and IV. In contrast to the other sulfonamides, dorzolamide is a potent inhibitor of isoenzymes II and IV, and a weak inhibitor of isoenzyme I [ 10]. Isoenzyme II is thought to play a major role in aqueous humor secretion. 

Dorzolamide hydrochloride, marketed as a 2% ophthalmic solution, was approved for the treatment of elevated intraocular pressure in patients having ocular hypertension or open-angle glaucoma. 

Introduction of the C2 sulfonamide is accomplished via sulfonylation with chlorosulfonic acid, conversion to the sulfonyl chloride using thionyl chloride, and amidation using concentrated ammonium hydroxide in tetrahydrofuran. Reduction of the 4-acetamido compound using borane-tetrahydrofuran complex provides the 4-ethylamino derivative. The 45,65-frans diastereomer is selectively crystallized as its maleate salt from acetone in the presence of the unwanted 4R,6S-cis diastereomer. Neutralization of the maleate salt and extraction of the free base in ethyl acetate, followed by formation of the hydrochloride salt, yields crude dorzolamide hydrochloride. 

Crude dorzolamide hydrochloride is purified by dissolution in water with heating, and treatment with activated carbon. The final crystallization step provides dorzolamide hydrochloride in the desired form. 

Scheme 1. Multi-step synthesis of dorzolamide hydrochloride.

Form I is the polymorph typically produced by the synthetic process described in section 2.0 of this profile. Isolation of dorzolamide hydrochloride from organic solvents (i.e., -propanol) can result in the formation of either Form 1 or Form II, while crystallization from water leads to Form II. 

Figure 1. X-ray powder diffraction pattern of dorzolamide hydrochloride, Form I.

Figure 3. Differential scanning calorimetry thermogram of dorzolamide hydrochloride.

Potentiometric titration studies were used to obtain values for the two ionization constants of dorzolamide hydrochloride. The first of these yielded pK, = 6.35, corresponding to the secondary amino functional group. The second ionization corresponded to sulfonamido group, for which pK 2 ... 

Equilibrium Solubilities of the Two Polymorphs of Dorzolamide Hydrochloride in Various Solvents... 

Figure 4. pH dependence of the equilibrium solubility of dorzolamide hydrochloride, Form 1. 

Figure 5. Temperature dependence of the amine pK values of dorzolamide hydrochloride.

The ultraviolet absorbance spectrum of dorzolamide hydrochloride was obtained using an AVIV Model USDS UVA IS spectrophotometer, with the compound being dissolved in 0.1 N methanolic hydrochloric acid. As evident in Figure 6, the spectrum is characterized by an absorbance maximum at 255 nm. The a ° ° value for this band was calculated to be approximately 357. 

Figure 6. Ultraviolet absorption spectrum of dorzolamide hydrochloride.

Assignments for the Major Absorptions of Dorzolamide Hydrochloride in the Infrared Spectral Region... 

Assignments for the Resonance Bands observed in the H-NMR Spectrum of Dorzolamide Hydrochloride... 

The carbon-13 nuclear magnetic resonance spectrum of a 4.7% (w/v) solution of dorzolamide hydrochloride was obtained in deuterated dimethyl sulfoxide, and is shown in Figure 9. The spectrum was recorded using a Brucker model AM-400 NMR spectrometer. The band assignments were referenced relative to dimethyl sulfoxide-ds (39.5 ppm), and the carbon atom assignments (using the same numbering system as just described) are collected in Table 5. 

When the stability of dorzolamide hydrochloride was studied in 2% ophthalmic solutions over two years, photodegradation was not observed. However, when solutions were exposed to daylight, a degradant identified as the 45,65 de-ethylated analog was formed. 

Dorzolamide Hydrochloride is an inhibitor of human carbonic anhydrase II. The inhibition of carbonic anhydrase in the ciliary processes of the eye decreases the secretion of aqueous humor, with a resulting reduction in intraocular pressure. The drug is formulated as an ophthalmic solution, and administered topically as eyedrops. 

Dorzolamide hydrochloride is commercially available as a 2% ophthalmic solution. In man, it is well tolerated, and topical administration into the... 

Figure 11. Degradation of dorzolamide hydrochloride as a function of pH after 2 years of storage at 25"C,...

Opfitfialmic Solution-. 2% dorzolamide hydrochloride and 0.5% timolol maleate (Cosopt). 

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