HK1193130B - Reactive dyes for contact lenses - Google Patents

Description

Reactive dyes for contact lenses

This application claims the benefit of prior U.S. provisional patent application No. 61/509,388, filed 2011, 7, 19, § 119(e), which is incorporated herein by reference in its entirety.

Technical Field

The technical field of the present invention is reactive dyes for contact lenses.

Background

The colorants used to make tinted soft contact lenses typically dissolve out and the lenses lose their original tint when subjected to sterilization conditions or during long term storage. There is a need for suitable colorants that can withstand the processing requirements for manufacturing contact lenses. Furthermore, the purity levels of commercially available colorants are typically extremely low, and the use of such colorants results in a large amount of undesirable salts or impurities in the contact lens formulation. For example, reactive dyes (reactive blue19 (reactive blue19, RB19)) are commonly available with a dye content of less than 50%, while salts such as sodium sulfate and other organic materials make up the remainder of the material. The presence of foreign substances in the dye affects the polymerization kinetics and the overall yield.

Disclosed herein are methods of making high purity reactive dyes that can be incorporated into polymerizable compositions without impurities that can negatively impact kinetics and overall polymerization. Background publications include U.S. patent No. 4,468,229, U.S. patent No. 4,559,059, U.S. patent No. 5,470,932, U.S. patent No. 5,944,853, U.S. patent No. 6,149,692, U.S. patent No. 7,216,975, and U.S. patent No. 7,659,325.

Disclosure of Invention

Provided herein is a method of preparing a polymerizable monomer-dye compound. The method comprises preparing a reaction mixture under substantially anhydrous reaction conditions by combining a monomer, a reactive dye, and a base to form a reaction product comprising the monomer-dye compound, wherein the monomer comprises a reactive pendant group that covalently bonds to the dye during reaction to form the polymerizable monomer-dye compound.

Examples of monomers useful in the above-described methods include acrylate-containing monomers (e.g., hydroxyethyl methacrylate), Si-O-containing monomers, and monomers containing polymerizable groups (e.g., vinyl ether, vinyl ester, allyl ester, vinyl amide polymerizable groups). Examples of reactive side groups of the monomers include hydroxyl, amino, or thiol groups.

The reactive dye used in the above process may comprise an ethylsulfonyl sulfate, halotriazine (halotriazine) group, or vinyl group, which reacts with the reactive pendant group of the monomer to form a covalent bond between the monomer and the dye. Exemplary reactive dyes that may be used in the method include RB19, RB4, or RB 69.

Exemplary bases that can be used in the above process include NaOH or K₂CO₃Or NaH or NaNH₂Or any combination thereof.

In one method, the reactive dye is RB19, the base is NaH or NaOH, and the monomer is HEMA in a molar amount of at least 5 times the reactive dye.

In one approach, the monomer and reactive dye may be added to the reaction mixture in a molar ratio of about 1:1 to about 6:1, respectively, or about 2:1 to about 4:1, respectively.

The reactive dye and the base may be added to the reaction mixture in a molar ratio of about 1:2 to about 4:1, respectively, or about 1:1 to about 2:1, respectively.

In one method, the monomer and reactive dye are added to the reaction mixture in a molar ratio of about 1:1 to about 6:1, respectively; and the reactive dye and the base are added to the reaction mixture in a molar ratio of about 1:2 to about 4:1, respectively.

In one method, the reactive dye and base are mixed together in the reaction mixture until at least 90% or 98% of the reactive dye is converted to an intermediate product, and then the monomer is added to the reaction mixture. In a particular method, RB19 and NaH were mixed together until at least 90% of RB19 was converted to an intermediate product, and then HEMA was added to the reaction mixture.

In one method, the reactive dye and the base are mixed together in a molar ratio of about 1:1 to about 6:1, respectively, until at least 90% of the reactive dye is converted to an intermediate product, and then the monomer is added to the reaction mixture.

In one method, a reactive dye and NaH or NaNH₂Or any combination thereof, in a molar ratio of dye to base of about 1:2 to about 4:1 and reacted under anhydrous conditions until at least 90% of the reactive dye is converted to an intermediate product. The monomers are then added to the reaction mixture in a molar ratio of monomer to reactive dye of about 1:1 to about 6:1, respectively.

In one method, a reactive dye comprising an ethanesulfonyl sulfate group and NaH or NaNH₂Or any combination thereof, in a molar ratio of dye to base of about 1:2 to about 4:1 and reacted under anhydrous conditions until at least 90% of the reactive dye is converted to an intermediate product. The monomers are then added to the reaction mixture in a molar ratio of monomer to reactive dye of about 1:1 to about 6:1, respectively.

In one method, RB19 and NaH or NaNH₂Or any combination thereof, in a molar ratio of dye to base of about 1:2 to about 4:1 and reacted under anhydrous conditions until at least 90% of RB19 is converted to an intermediate product. Hydroxyethyl methacrylate (HEMA) was then added to the reaction mixture in a molar ratio of HEMA to RB19 of about 1:1 to about 6:1, respectively.

In any of the foregoing methods, the reaction mixture may be mixed at a temperature of about 15-45 ℃, about 20-30 ℃, or at room temperature; and the reaction may be carried out for about 1 to about 6 hours or about 2 to 5 hours.

Any of the foregoing methods may further comprise purifying the reaction product to obtain a monomer-dye compound having a purity level of at least 90%. In one example, the purifying comprises mixing the reaction product with silica gel and passing the reaction product and silica gel mixture through a silica gel column.

Also provided herein are polymerizable monomer-dye compounds prepared by any of the foregoing methods, contact lenses comprising the polymerizable dye compounds, and a method of manufacturing contact lenses comprising polymerizing a polymerizable formulation comprising the polymerizable monomer-dye compounds to form contact lenses.

Drawings

FIG. 1 depicts a reaction scheme for making a polymerizable monomer-dye compound according to the present invention.

Detailed Description

We have discovered an improved method of making polymerizable reactive dyes for contact lens formulations wherein the reactive dyes are reacted with monomers in the presence of a base under substantially anhydrous conditions. The reaction product comprises a monomer-dye conjugate that can be readily purified to a high purity final product suitable for incorporation into a polymerizable contact lens formulation.

The monomers used in the method include a (i.e., one or more) reactive pendant group that is capable of reacting with the reactive dye to form a covalent bond between the monomer and the dye. Suitable pendant reactive groups include hydroxyl, thiol, or amino groups that are covalently linked to the reactive group of the reactive dye in the presence of a base to form an ether, thioether, or amino linkage, respectively, between the monomer and the dye. As used herein, the term "monomer" refers to any molecule capable of reacting with other identical or different molecules to form a polymer or copolymer. Thus, the term encompasses polymerizable prepolymers and macromers, which are not size-limited unless otherwise specified. The monomer comprises one or more polymerizable moieties such that after formation of the monomer-dye compound, at least one polymerizable moiety remains for incorporation of the monomer-dye compound into a polymer. Typically the monomer is monofunctional, meaning that it contains only one polymerizable moiety. However, multifunctional (e.g., difunctional and trifunctional) monomers may also be used, in which case the resulting monomer-dye compound may act as a crosslinker in the polymerizable formulation.

In one example, the monomer is an acrylate-containing monomer, meaning that it contains a polymerizable acrylate functionality (e.g., methyl methacrylate, acrylate, and the like). In one example, the acrylate monomer has a polymerizable methacrylate group. Numerous suitable acrylate monomers comprising one or more hydroxyl, thiol, or amino reactive pendant groups are known. Exemplary acrylate monomers include methacrylic acid, acrylic acid, 2-hydroxybutyl methacrylate (HOB), 2-hydroxyethyl acrylate, glycerol methacrylate, glycerol dimethacrylate, 2-hydroxyethyl methacrylate (HEMA), 2-hydroxypropyl acrylate, 3-hydroxypropyl acrylate, 4-hydroxybutyl acrylate, N-hydroxyethyl methacrylamide, N-bis (2-hydroxyethyl) methacrylamide, 2-aminoethyl methacrylate, N- (3-aminopropyl) methacrylamide, N- (2-aminoethyl) methacrylamide and 2-mercaptoethyl methacrylate.

Other useful suitable monomers include polymerizable vinyl groups such as vinyl ether, vinyl ester, allyl ester, or vinyl amide polymerizable groups. Examples of such monomers include 1, 4-Butanediol Vinyl Ether (BVE), Ethylene Glycol Vinyl Ether (EGVE), and diethylene glycol vinyl ether (DEGVE).

In other examples, the monomers comprise Si-O groups, referred to herein as Si-O-containing monomers. Useful examples of Si-O containing monomers include MCS-MC12 (Gelest, Morrisville, Pa.), 3-methacryloxy-2-hydroxypropoxy) propylbis (trimethylsiloxy) methylsilane (SiGMA), methacryloxy-2-hydroxypropyl TRIS- (trimethylsiloxy) silane (TRIS-OH), Polydimethylsiloxane (PDMS) silanol, and 3' -TRIS (trimethylsiloxy) silylpropyl-3- (2-hydroxyethyl) carbonyl crotonate.

Reactive dyes useful in the process are well known in the art. In one example, the reactive dye comprises a reactive group, which is a sulfatoethylsulfonyl group, a halotriazine group, or a vinyl group. Exemplary dyes include ramazol black b (remazol black b) and reactive blue dyes such as reactive blue19 (RB19), reactive blue 4(RB4), and reactive blue 69(RB 69). Other suitable reactive dyes include reactive blue 140, reactive blue 163, reactive blue 109, reactive yellow 86, reactive yellow 22, reactive yellow 7, reactive orange 4, reactive red 11, reactive red 1, reactive red 2, reactive red 6, and Prussian Black MX-CWA (Procion BlackMX-CWA). Typically, commercially available reactive dyes are less than 90% or 80% pure. The reactive dyes may be used directly in the process or may be purified prior to use. An exemplary purification method is described in example 1. In one method, the reactive dye is purified using methanol. This can be accomplished by mixing the dye with methanol for at least 1 hour at about 1:5 parts to about 1:50 parts, respectively, and filtering and drying the dye. The reactive dye may be purified to at least 85%, 90% or 95% purity as determined by peak area of HPLC reading. In a particular method, the reactive dye is RB19 of at least 85%, 90%, or 95% purity. Throughout this specification, unless the context indicates otherwise, when a qualifier precedes a first numerical value in a series of numerical values, the qualifier is intended to implicitly precede each numerical value in the series. For example, in the purity classes described above, it is intended that the qualifier "at least" implicitly precedes the values 90% and 95%.

Any base capable of acting as a catalyst in the reaction to obtain a covalent bond between the dye and the monomer may be used. Examples of suitable bases include NaH, NaNH₂NaOH and K₂CO₃. In one example, the base is a sodium salt (e.g., NaH, NaNH)₂NaOH, etc.). In another example, a base is used that results in the formation of a reaction product that is substantially free of in situ generated water. Examples of such bases include NaH and NaNH₂. As used herein, a reaction product that is substantially free of in situ water comprises less than 0.5% in situ water. When a base is used that produces in situ water, a desiccant (e.g., anhydrous Na) may be added₂SO₄) Is added to the reaction to maintain substantially anhydrous reaction conditions. Is substantially free ofWater reaction conditions mean that the reaction mixture contains less than 2% water or less than 1% or 0.5% water. In a specific example, the reactive dye is RB19, the monomer is HEMA and the base is NaH.

In one example, the reactive dye is mixed with a base to form an intermediate product, and then the monomer is added to the reaction mixture. The percentage of conversion of the reactive dye to the intermediate product can be monitored by Thin Layer Chromatography (TLC). In one example, the monomers are added to the reaction mixture after at least about 90%, 95%, 98%, or 99% of the reactive dye has been converted to an intermediate product (as determined by TLC or other suitable chromatographic method). For example, in reaction 12 described in example 2 below, RB19 was mixed with a solvent followed by the addition of a strong base, which resulted in the conversion of RB19 to an intermediate product (believed to be RB 19-vinyl sulfone). Thin Layer Chromatography (TLC) was used after the reaction until all RB19 was completely converted to the intermediate product. Then, monomer (HEMA) was added. After evaporation of the solvent and prior to any workup or column purification, the final reaction product of reaction 12 contained about 70% RB19-HEMA.

In one example, the molar amount of monomer added to the reaction mixture is at least 5 times, 10 times, 15 times, or 20 times that of the reactive dye. In a specific example, the reactive dye is RB19, the base is NaH and the monomer is HEMA, the monomer being added in at least 5 times the molar amount of RB 19. In other examples, the monomers are added to the reaction mixture in a molar ratio of monomer to reactive dye of about 1:1 to about 6:1, respectively, or about 2:1 to about 4:1, respectively. Additionally or alternatively, the molar ratio of reactive dye to base in the reaction mixture is from about 1:4 to about 4:1, respectively, or from about 1:2 to about 4:1, respectively, or from about 1:1 to about 3:1, respectively, and in one example from about 1:1 to about 2:1, respectively.

In one example, at least 95%, 98%, or 99% of the reactive dye is converted to an intermediate product in the presence of a base, and then monomers are added to the reaction mixture in a molar ratio of monomer to reactive dye of about 1:1 to about 6:1, respectively, or about 2:1 to about 4:1, respectively.

The reactants can be mixed together at any temperature that allows the desired reaction to occur. In one example, the reaction occurs at about 15-45 ℃ or about 20-30 ℃ or at room temperature, where the temperature is based on the immediate ambient temperature at which the reaction occurs (rather than the actual temperature of the reaction mixture). The reaction is generally complete in about 1 to 6 hours or about 2 to 5 hours. In various examples, the reaction product comprises at least 50%, 55%, 60%, 70%, or 75% monomer-dye compound prior to any post-reaction treatment or purification.

After the reaction is complete, the reaction product may be purified using any suitable method or combination of purification methods to increase the monomer-dye compound purity to at least 90%, 95%, 97%, 98%, or 99%. Exemplary purification methods are described in examples 3-6 below. In one example, the reaction product is mixed with silica gel and then passed through a silica gel chromatography column.

The monomer-dye compounds are suitable for use as colorants for polymeric medical devices, including ophthalmic devices, such as silicone hydrogel contact lenses or traditional HEMA-based hydrogel contact lenses. The monomer-dye compound can be added directly to a polymerizable composition comprising at least one additional polymerizable monomer, which is then polymerized to render the monomer-dye a constituent of the resulting polymer, imparting color thereto. The monomer-dye is typically added to the polymerizable formulation in an amount of about 0.001wt.% to about 0.5wt.%, relative to the weight of all polymerizable ingredients in the formulation. For silicone hydrogel contact lens formulations, the monomer-dye may be added to the formulation in an amount of about 0.005wt.% to about 0.05 wt.%. Examples of polymerizable formulations for silicone hydrogel contact lenses are described in U.S. patent No. 7,750,079 and U.S. patent No. 7,572,841, which are incorporated herein by reference. The colorants used in the formulations described in these patents may be replaced by the monomer-dyes described herein. Accordingly, provided herein is a method of manufacturing a contact lens, the method comprising: (i) preparing a polymerizable formulation comprising a monomer-dye compound prepared as described herein and at least one additional polymerizable monomer; and (ii) polymerizing the polymerizable formulation to form a contact lens. In a particular example, the monomer-dye is RB19-HEMA, and the at least one additional polymerizable monomer is a Si-O-containing monomer.

As is apparent from the disclosure of the present application in its entirety, including the claims structures and specific examples, the exemplary components of the methods of preparing polymerizable monomer-dye compounds disclosed herein can generally be combined in embodiments of the present invention. For example, one skilled in the art will recognize that the method of preparing the polymerizable monomer-dye compound of the present invention advantageously comprises: combinations of the exemplary monomers disclosed herein with the exemplary reactive dyes disclosed herein and with the exemplary bases disclosed herein.

Thus, the exemplary acrylate monomers, vinyl-containing monomers, or Si-O group-containing monomers disclosed in the above paragraphs are advantageously combined with any of the reactive dyes disclosed above in the method of the present invention. For example, HEMA or EGVE or SiGMA may be combined with any of the reactive dyes disclosed above, in particular RB19 or RB4 or RB 69.

Advantageously, the exemplary monomers disclosed in the above paragraph are combined with any of the exemplary bases disclosed in the above paragraph. For example, the exemplary acrylate monomers, vinyl-containing monomers, or Si — O group-containing monomers disclosed in the above paragraphs can be used in combination with any one or more of the bases disclosed above, particularly in combination with NaH or NaOH.

Similarly, the exemplary reactive dyes disclosed in the above paragraphs may be combined with any of the exemplary bases disclosed in the above paragraphs. For example, RB19 or RB4 or RB69 can be combined with any one or more of the bases disclosed above, particularly with NaH or NaOH.

Furthermore, the exemplary monomers disclosed in any of the above paragraphs are advantageously combined with any of the reactive dyes disclosed above and any of the bases disclosed above in the method of the present invention. Thus, the process of the invention may optionally include HEMA or EGVE or SiGMA in combination with both (i) RB19 or RB4 or RB69 and (ii) a base such as NaH or NaOH.

Additionally, it is to be understood that these components can be combined in any of the relative molar ratios described in the examples above. Thus, for example, the methods of the invention can optionally include HEMA or EGVE or SiGMA in combination with both (i) RB19 or RB4 or RB69 and (ii) a base such as NaH or NaOH, wherein the monomer and reactive dye are combined in a molar ratio of about 1:1 to about 6:1, respectively, and/or the reactive dye and base are combined in a molar ratio of about 1:2 to about 4:1, respectively.

As described above and in the specific examples, it has been found that the combination of preferred monomers, reactive dyes and/or bases of the present invention provides monomer-dyes with advantageous properties for use in methods of manufacturing contact lenses.

The following examples illustrate certain aspects and advantages of the present invention, which should not be construed as limiting. Unless otherwise indicated, any% amounts provided herein are based on total weight. Furthermore, the terms or phrases "a" or "an" are intended to encompass "one or more," such as two, three, four, or more.

Example 1: purification of reactive blue19

RB19 was purified using methods A-C described below.

The method A comprises the following steps: 10g of RB19 (Sigma-Aldrich) with a purity of about 78% (HPLC at 254 nm) were dissolved in 50ml of DI water. 1 liter of THF was added to the RB19 solution and mixed well by stirring for 30 minutes. The mixture was filtered, and the resulting solid was mixed with 50ml of methanol, and then precipitated using 500ml of diethyl ether. The mixture was filtered and washed with ether, and then dried to give about 8.0g of a blue powder. HPLC analysis showed 92.5% purity.

The method B comprises the following steps: 10g of RB19 (Sigma-Aldrich) with a purity of about 78% (HPLC at 254 nm) were dissolved in 100ml of methanol and stirred at room temperature for 30 minutes. 400ml of ethyl acetate was added to the RB19 solution and mixed well by stirring for 30 minutes. The mixture was filtered and the resulting solid was further washed with 40ml of tetrahydrofuran and then dried to give about 9.0g of a blue powder. HPLC analysis showed 90.7% purity.

The method C comprises the following steps: 70g of commercial RB19 (having a dye content of about 50% and a purity of 84%) was purified by stirring with 20 volumes of methanol for 4 hours, filtering, and drying thoroughly under vacuum for 18 hours. Purified RB19(50g) was obtained in 71% yield and 96% purity.

Example 2: synthesis of RB19-HEMA Using Anhydrous conditions and Strong bases

For each of reactions 1-11, summarized in Table 1, is>The round-bottomed flask was pre-dried at 110 ℃. The HEMA was pre-dried at 170 ℃ using 3A molecular sieves. To each flask, under nitrogen, were added RB19, 4-Methoxyphenol (MEHQ), dried HEMA, and anhydrous NaOH or K₂CO₃. In some reactions (i.e., 3, 6, and 7), NaSO is added₄As a desiccant. The reaction mixture was stirred under nitrogen in a 40 ℃ oil bath. For reactions 1-6, about 50-60% of RB19 formed the undesirable product RB19-OH (as determined using HPLC at 585 nm), and about 40-50% formed RB19-HEMA. In reaction 4, which has the shortest reaction time (30 minutes), there is one peak containing about 1.5% of intermediate RB 19-vinyl sulfone (RB 19-VS).

For reaction 12 of Table 1, 50g of purified dry RB19 was placed in a 1L three-neck round bottom flask. 180ml DMF was added and the mixture was stirred for 30 minutes. 100 mg of NaH was added in portions, and stirred at room temperature for 1 hour. The reaction was followed by Thin Layer Chromatography (TLC) using 10% methanol in dichloromethane. Additional portions of 50mg NaH were added until all RB19 had been completely converted to the intermediate RB19-VS (assumed). Next, 29ml hema was added dropwise to the mixture at room temperature using an addition funnel. The resulting mixture was stirred at room temperature until TLC showed complete disappearance of the intermediate product (typically 3-4 hours). The mixture was then transferred to a 1L round bottom flask and placed under a high vacuum at 70 ℃ to remove most of the DMF solvent.

TABLE 1

In reaction 9, after 120 minutes at 40 ℃, the reaction was continued for 45 minutes at room temperature.

In the above reaction, sodium sulfate was used as a drying agent. MEHQ to inhibit potential polymerization of HEMA; no HEMA polymerization was detected under any of the conditions tested. Unreacted HEMA and other impurities can be removed from the reaction product using one or more of the methods described in examples 3-6 to yield high purity RB19-HEMA.

Example 3: RB19-HEMA was purified by precipitation and column chromatography.

For the 1g scale RB19 reaction, 50ml thf was added to the reaction product and stirred for 10 minutes. Then 50ml of hexane were added and stirred for another 10 minutes. The mixture was sealed and refrigerated for 2 hours. The mixture was then filtered and the resulting solid was loaded onto a silica gel column for purification. The process effectively removes a substantial portion of the unreacted HEMA in the mixture. HEMA can also be removed using another precipitation solvent (e.g., diethyl ether).

Example 4: RB19-HEMA was purified by ethyl acetate/water wash.

About 10 times the volume of EtOAc used in the reaction was added to the reaction product. The mixture was transferred to a separatory funnel and washed with saturated NaCl solution. During washing, most of the putative RB19-OH precipitated on the separatory funnel wall. The washed EtOAc phase was dried over sodium sulfate. After removal of all solvents by rotary evaporator and drying of the product under vacuum, a dark slurry of crude RB19-HEMA was obtained. In addition to RB19-HEMA, the slurry contained unreacted HEMA and unknown impurities (shown under HPLC at 254 nm). Four times the volume of HEMA ether or THF/hexane (3:7) was added to the slurry to precipitate a solid stain. The solid was filtered and rinsed with a small amount of ether or THF/hexane. This washing step removed unreacted HEMA and impurities.

Example 5: RB19-HEMA was purified by column chromatography.

The reaction product from reaction 11 in example 2 above was loaded directly onto an 80g silica gel column. For containing in CH₂Cl₂Or CHCl₃0 to 15% MeOH in. The crude reaction product contained about 35% RB19-HEMA, 51% RB19-OH (hypothetical) and HEMA solvent. After column purification, 0.133g of RB19-HEMA with a purity of 98% (HPLC at 254nm and 585 nm) were obtained.

Example 6: RB19-HEMA was purified by column chromatography and precipitation.

The crude reaction product of example 2, reaction 12, was mixed with 50g of silica gel. The mixture was transferred to the top of a chromatography column packed with 400g of silica gel in 1 LDCM. The column was eluted with 6% methanol in DCM (9L total). When the blue product eluted, it was collected in 40ml fractions, 4 liters in total. Each fraction was checked by TLC. Fractions containing RB19-HEMA were combined and concentrated to give about 8.5g of a blue product. The product purified via the column was stirred in 100ml of an ether-ethyl acetate-hexane (8:1:1) mixture for 18 hours; the procedure was repeated until the filtered product had an acceptable purity as determined by NMR and HPLC. As determined by HPLC, 8.2g of the final product with 95.6% RB19-HEMA was obtained.

Applicants specifically incorporate the entire contents of all cited references into this disclosure. Further, when an amount, concentration, or other value or parameter is given as either a range, preferred range, or a list of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. Where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof and all integers and fractions within the range. When defining ranges, it is not desired that the scope of the invention be limited to the specific values recited.

Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims and their equivalents.

Claims (17)

1. A method of preparing a polymerizable monomer-dye compound comprising:

combining a monomer, a reactive dye, and a base under substantially anhydrous reaction conditions to form a reaction product comprising the monomer-dye compound, wherein the monomer comprises a pendant reactive group covalently bonded to the reactive dye during the reaction to form the polymerizable monomer-dye compound,

wherein the reactive pendant group is a hydroxyl group, an amino group, or a thiol group, which forms an ether bond, an amino bond, or a thioether bond between the monomer and the dye, respectively.

2. The method of claim 1, wherein the monomer is hydroxyethyl methacrylate.

3. The method of claim 1, wherein the monomer is a Si-O containing monomer.

4. The method of claim 1, wherein the monomer and the reactive dye are present in the reaction mixture in a molar ratio of 1:1 to 6:1, respectively.

5. The method of claim 1, wherein the monomer is present in a molar amount that is at least 5 times the molar amount of the reactive dye.

6. The method of claim 1, wherein the reactive dye comprises an ethylsulfonyl sulfate, a halotriazine group, or a vinyl group that reacts with the reactive pendant group of the monomer to form the covalent bond between the monomer and the dye.

7. The method of claim 1, wherein the reactive dye is RB19, RB4, or RB 69.

8. The method of claim 1, wherein the reactive dye is RB19 having a purity of at least 90%.

9. The method of claim 1, wherein the base is NaOH, or K₂CO₃Or NaH or NaNH₂Or any combination thereof.

10. The method of claim 1, wherein the monomer is HEMA, the reactive dye is RB19 and the base is NaH.

11. The method of claim 10, wherein the RB19 and NaH are mixed together and at least 90% of the RB19 is converted to an intermediate product prior to adding the HEMA to the reaction mixture.

12. The method of claim 1, wherein the reaction mixture is mixed at a temperature of 15-45 ℃.

13. The method of claim 1, wherein the reaction mixture is mixed at a temperature of 20-30 ℃.

14. The method of claim 1, wherein the reaction lasts from 1 hour to 6 hours.

15. The method of claim 1, wherein the reaction conditions comprise less than 2% water.

16. The method of claim 15, wherein the reaction conditions comprise less than 1% water.

17. The method of claim 15, wherein the reaction conditions comprise less than 0.5% water.