Method ophthalmic solutions

In general, aqueous ophthalmic solutions are manufactured by methods that call for the dissolution of the active ingredient and all or a portion of the excipients into all or a portion of the water and the sterilization of this solution by heat or by sterilizing filtration through sterile depth or membrane filter media into a sterile receptacle. If incomplete at this point, this sterile solution is then mixed with the additional required sterile components, such as previously sterilized solutions of viscosity-imparting agents, preservatives, and so on, and the batch is brought to final volume with additional sterile water. 

On the basis of freezing point depression values, the USP includes a method for rapidly adjusting isotonicity of ophthalmic solutions. Since depression of freezing point depends upon the number of particles of solute(s) in solution, a proportion can be set up to solve for the volume of isotonic solution... 

Cherkaoui, S., Mateus, L., Christen, P., and Veuthey, J.-L. (1997). Development and validation of a capillary zone electrophoresis method for the determination of atropine, homatropine and scopolamine in ophthalmic solutions.. Chromatogr. B 696(2), 283-290. 

G. Parhizkani, R. B. Miller, and C. Chen, A stability-indicating HPLC method for the determination of benzalkonium chloride in phenylephrine HG 10% ophthalmic solution, J. Liquid Chromatogr., 78 553 (1995). 

An indirect polarographic method for the determination of EDTA in eyewash and ophthalmic solutions has been reported [16]. The method is based on the decrease of the polarographic wave of Cd(II) or Zn(II). A similar method involving the use of Bi(III) was also reported [17]. 

A colorimetric method based on the inhibitory effect of EDTA on the Mn(II) catalyzed oxidation of malachite green by periodate was reported [32]. An alternative method based on using Fe(III) instead of Mn(II) was proposed [33]. The reduction of the absorbance of Bi(III) bromo-pyrogallol red tenside ternary complex upon the addition of EDTA has been exploited for its determination. Calibration curves obtained at 650 nm were linear over the range of 0.2-6 pg/mL of EDTA [34]. EDTA in ophthalmic solutions could be assayed by spectrophotometric titration using Mg(II) as the titrant and Arsenazo I as the indicator. The working range was 0.05-2 pg/mL [35]. 

A sample chromatogram for the LC conditions used for the determination of pilocarpine in pilocarpine ophthalmic solutions is shown in Figure 12.11. This is atypical since there is a very long analysis time, due to setting up the method to determine degradation products. However it is typical in that, for commercial samples containing 2%, 1% and 0.5% pilocarpine, RSDs in the range 3.2-4.1% were considered to be excellent. 

Products can be manufactured as sterile by different methods known as aseptic processing and terminal sterilization. Aseptic processing involves passing the ophthalmic solution through a 0.2 pm filter in order to rid the solution of all bacteria. The solution is then filled into sterile ophthalmic containers under sterile conditions. This assures a sterile product. 

Miller, R.B. Chen, C. A stability-indicating HPLC method for the determination of 17P-estradiol-3-phosphate in an ophthalmic solution. Chromatographia, 1995, 40, 204-206... 

Only the Japanese Pharmacopoeia [4] and USP [3] set limits for levels of particles in eye drops. The Japanese Pharmacopoeia requires that eye drops after filtration and assessment with a microscope must have a maximum of 1 particle of 300 pm or larger per millilitre. The requirements of the USP are cmisiderably stricter. Chapter 789 (Particulate matter in Ophthalmic Solutions) requires that maximally 50 particles of >10 pm and maximally 5 particles of >25 pm per mL eye drop fluid may be present. The method used is the light obscuration method. 

Elrod, L., T. G. Golich, J. A. Morley, Benzalkonium chloride in eye care products by HPLC and solid-phase extraction or on-line column switching, J. Chromatogr., 1992,625, 362-367. Parhizkari, G., G. Delker, R. B. Miller, C. Chen, Stability-indicating HPLC method for determination of benzalkonium chloride in Tramadol ophthalmic solution, Chromatographia, 1995,40,155-158. 

The class II methods involve the calculation of a quantity of water needed to make an isotonic solution for a given amount of drug, followed by dilution with an isotonic solution to make up the volume. These methods were developed to enable pharmacists to prepare parenteral and ophthalmic formulations with simplicity and ease. 

---