Patent Grant
11591661
The milk sugar lactose can be produced by concentrating cheese whey or de-proteinized cheese whey, cooling the concentrate to force crystallization of the lactose contained in the whey, separating the crystals from the balance of the whey constituents, purifying the crystals through washing with water, and drying the washed crystals.
Dried lactose product obtained from dairy processing, referred to herein as edible grade lactose, may be used as an energy source, for example, in simulated milk formulations for infants and for baby animals and is used as an ingredient in various confections. Lactose may also be used in pharmaceutical applications, for example, as an excipient in pharmaceutical formulations. However, the purity of lactose required by the pharmaceutical industry is higher than the purity associated with edible grade lactose.
The impurities found in edible grade lactose that typically render it unsuitable for pharmaceutical applications include insoluble impurities and riboflavin. The insoluble impurities may include calcium salts and denatured proteins. Riboflavin, which may be found in milk, whey and permeate, may adsorb to the surface of lactose crystals and impart a yellow color to dried edible grade lactose and to solutions of edible grade lactose. Pharmaceutical grade, high purity lactose may be produced by removing riboflavin and the insoluble impurities found in edible grade lactose. Pharmaceutical grade lactose is substantially white and forms a clear, colorless aqueous solution.
A technique for purifying edible grade lactose may include adding activated carbon to a solution of edible grade lactose to remove the riboflavin by adsorption onto the activate carbon, followed by filtering the solution to remove the insoluble impurities and the activated carbon, evaporating the purified solution, crystallizing lactose, and drying the lactose crystals. Riboflavin may also be removed from lactose using a food grade adsorbent resin such as Amberlite FPX66 resin (Rohm and Hass, Philadelphia, Pa.).
The traditional process for producing high purity (e.g. pharmaceutical grade) lactose uses activated carbon and is labor intensive. Furthermore, the filtration step required to remove the activated carbon requires pre-coating a filter with a filter aid. The filter aid along with the activated carbon and insoluble impurities are solid waste by-products which require disposal. Any voids in the filter aid or a malfunction of the vacuum filter can allow contamination of the previously clarified batch of lactose.
Food-grade adsorbent resins such as Amberlite FPX66 are not currently FDA-approved for production of high purity lactose intended to be consumed, for example, in infant formula, pharmaceutical formulations, and other such products.
The present disclosure describes efficient and commercially useful systems and techniques for purifying lactose, for example, edible grade lactose, to obtain high purity lactose suitable for edible and pharmaceutical applications.
In one embodiment, the disclosure describes a system for purifying a supply stream including lactose. The system includes a clarification system configured to remove insoluble impurities from the supply stream to produce a clarified stream. The system also includes an adsorption system that includes an adsorbent resin. The adsorbent resin in the adsorption system removes colorants or contaminants, for example, riboflavin, from the clarified stream, to decolorize the clarified stream.
In another embodiment, the disclosure describes an example technique for purifying a supply stream including lactose. The example technique includes clarifying the supply stream by removing insoluble impurities to produce a clarified stream. The example technique also includes mixing the clarified stream with an adsorbent resin to produce a decolorized stream.
The details of one or more aspects of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
The foregoing and other aspects of this invention are made more evident in the following Detailed Description, when read in conjunction with the attached Figures.
It should be understood the Figures present non-exclusive examples of the techniques disclosed herein.
Example systems and techniques per the disclosure may be used to prepare high purity lactose, for example, pharmaceutical-grade lactose. In some examples, systems and techniques according to the disclosure may be used to prepare high-purity products that may meet the requirements for regulatory approval. For example, the high purity products may meet requirements set forth in a pharmacopeia, for example, the U.S. pharmacopeia, EU pharmacopeia, or the Japanese pharmacopeia.
Example systems and techniques per the disclosure may include a clarification step, to remove calcium and other insoluble contaminants from the process stream. Without being bound by theory, reduction of the calcium and other insoluble contaminants is the first lactose purification step. In addition to purification, removal of the insoluble contaminants also produces a clarified lactose stream which will not plug downstream process stages, for example, an adsorption system.
A food-grade resin in an adsorption system (for example, in a packed-bed column) may be used to remove riboflavin from lactose solutions to produce pharmaceutical grade lactose. The packed-bed chromatography technique removes the need to repeatedly procure and supply fresh activated carbon. It also removes the need to further process the lactose solution to remove the spent carbon or filter aid, and eliminates the added cost and complications associated with disposing waste streams.
Various advantages are associated with the example systems and techniques per the disclosure. For example, the systems and techniques of the disclosure avoid issues associated with handling activated carbon; eliminate costs associated with purchasing activated carbon and filter aids; allow for continuous processing which can take full advantage of process automation; lower labor costs; eliminate by-products which require solid waste disposal (e.g., spent carbon and filter aids); produces high yields (almost 100%) of pharmaceutical grade lactose from edible grade-grade lactose by producing negligible losses (losses only limited to those normally associated with product handling in a hygienic process). An advantage of example systems per the present disclosure may include operation at high solids (e.g., 40% total solids) thereby eliminating the traditional requirement for evaporating the purified lactose stream prior to the final crystallization.
In some examples, supply stream 12 may include solid lactose crystals suspended in a fluid, for example, water, and system 10 may optionally include a crystal solubilizing system (not shown). The crystal solubilizing system may dissolve the lactose crystals from supply stream 12 in water to produce a solution of lactose. For example, the crystal solubilizing system may include a tank, a mixer, or an inline mixer configured to agitate lactose crystals in water to cause lactose to dissolve into the water.
In some examples, supply stream 12 may include adding a base for adjusting the pH of the lactose solution to a basic pH. For example, supply stream 12 may include one or more of ammonium hydroxide (NH4OH), potassium hydroxide (KOH), and sodium hydroxide (NaOH), Na2CO3, NaHCO3, or another suitable inorganic or organic base. The base in the supply stream 12 may be in an amount sufficient to set pH within a predetermined pH range, without significantly altering the concentration of lactose in supply stream 12. The term “about” includes a pH deviation of ±0.5. For example, the pH may be between about 7 and about 11.
In some examples, supply stream 12 may be heated to maintain a temperature between about 60 and about 100° C., for example, at about 77° C. Without being bound by theory, presently available evidence indicates that the elevated temperature and basic pH will result in the precipitation of calcium salts. In some examples, calcium precipitation may be enhanced by the addition of an acid to provide an additional anion suitable for forming calcium precipitates, for example, carbonate (CO3−2), phosphate (PO4−3) or another suitable inorganic or organic acid anion. In some examples, the pH of supply stream 12 may be adjusted with a salt solution of high pH that contains anions which can cause calcium to precipitate. For example, a solution including sodium phosphates, sodium carbonates, and the like, may be used to raise the pH. Salts of these types may be used in combination with a base to induce the precipitation of calcium. Thus, various impurities may be primed for removal from supply stream 12.
System 10 includes a clarification system 14 for separating insoluble impurities from supply stream 12. In some examples, clarification system 14 may include a filter. For example, clarification system 14 may include any membrane filter capable of remaining stable at a relatively high pH and elevated temperature, for example, the pH and temperature ranges of supply stream 12 discussed above. In some examples, which are not intended to be limiting, the membrane filter may include one or more of cellulose-based, nylon, fluoropolymer, Teflon (also known as PTFE or polytetrafluoroethylene), polysulfone, polyethersulfone, modified polyethersulfone, or ceramic filtration media. In some examples, the filter has a predetermined molecular weight cutoff, for example, a cutoff that is sufficient to filter out calcium precipitates. For example, the filter may have a molecular weight cutoff in a range between about 10 kD and about 0.6 μm.
In some examples, clarification system 14 may include, in addition to a filter or instead of a filter, a centrifuge. For example, clarification system 14 may include a centrifugal clarifier that centrifuges supply stream to separate the insoluble impurities from supply stream 12, for example, based on the difference in the average density of the insoluble impurities.
Clarification system 14 receives supply stream 12, and separates predetermined impurities, for example, calcium precipitates, from supply stream 12 to filter supply stream 12 into a clarified stream 16 and a retentate stream 18. Clarified stream 16 includes lactose of higher purity compared to lactose in supply stream 12 and calcium and other insoluble impurities in a reduced concentration compared to supply stream 12. For example, clarified stream 16 may include a lower concentration of particulates, precipitants, or suspended impurities, compared to supply stream 12. In some examples, clarified stream 16 may include substantially no calcium ions. In some examples, clarified stream 16 is retained for further processing, or sent to a downstream processing stage. In some examples, retentate stream 18 may be recycled back for inclusion with the mother liquor by-product produced in the first crystallization process. Alternatively, the retentate containing primarily calcium salts can be diafiltered with water, dried and sold as milk minerals.
In some examples, system 10 may include a lactose recovery system 24 for recovering or refining lactose from retentate stream 18. For example, lactose recovery system 24 may receive a lactose feed 26 including lactose crystals, and may wash lactose crystals from lactose feed 26 with a wash medium. In some examples, lactose recovery system 24 may receive retentate stream 18 from clarification system 14, and use retentate from retentate stream 18 as the solution medium for dissolving lactose crystals from lactose feed 26. In some examples, lactose recovery system 24 may use retentate from retentate stream 18 mixed with fresh water as the wash medium.
Lactose recovery system 24 may include any suitable system for refining lactose crystals. Lactose recovery system 24 generates a refined stream 25 including washed lactose crystals. In some examples, refined stream 25 may include a wet cake, paste, or slurry of lactose. In some embodiments, refined stream 25 may be recirculated to supply stream 12, for example, after dissolving in water to generate a lactose solution. In some examples, at least a portion of refined stream 25 may not be recirculated to supply stream 12, and may instead be recovered as a side-product, for example, edible grade lactose.
In some examples, system 10 may include a melter that receives refined stream 25, and melts or dissolves lactose crystals in water to generate a lactose solution. In some examples, the melter may receive water from RO (reverse-osmosis), or purified water. In some examples, the lactose solution may be fed to supply stream 12. In some examples, one or both of lactose recovery system 24 and the melter may operate with clarification system 14 to ultimately recirculate retentate stream 18 into supply stream 12. Thus, in some examples, supply stream 12 may partly receive lactose from one or more of retentate stream 18, lactose feed 26, or a fresh supply of lactose from supply stream 12.
System 10 includes an adsorption system 20 for further purifying lactose in clarified stream 16 received from clarification system 14. Adsorption system 20 includes an adsorbent resin 22. In some examples, adsorbent resin 22 is capable of binding coloring agents from clarified stream 16 to decolorize clarified stream 16 to produce decolorized stream 28. For example, adsorbent resin 22 may be capable of binding riboflavin so that riboflavin is removed from a lactose solution passed over adsorbent resin 22. Riboflavin typically imparts a yellow color or tinge, so binding riboflavin reduces an intensity of at least a yellow component of the color of clarified stream 16 to produce decolorized stream 28. Adsorbent resin 22 may be disposed in adsorbent system 20 in any suitable configuration for sufficiently contacting clarified stream 16. For example, adsorbent system 20 may include a packed bed, a fluidized bed, or a stirred suspension of adsorbent resin 22. In some examples, adsorbent system 20 may include a stirred tank including adsorbent resin. Adsorbent resin 22 may include resin in the form of beads, pellets, rods, grains, or any other suitable form. While adsorbent resin 22 may be capable of decolorize a stream, for example, by removing colorants from the stream by adsorbing the colorants, adsorbent resin 22 may also purify the stream by removing other components, for example, contaminants. In some examples, the contaminants may include any components that may not be desired in the final lactose product.
In some examples, adsorbent resin 22 may include a food-grade or pharmaceutical-grade resin approved for use in systems that may process foods, pharmaceuticals, or other products for consumption. In some examples, adsorbent resin 22 may be a macroporous copolymer resin. In some examples, which are not intended to be limiting, the macroporous copolymer resin includes a monovinyl aromatic monomer and a crosslinking monomer, where the macroporous copolymer has been post-crosslinked in the swollen state in the presence of a Friedel-Crafts catalyst and functionalized with hydrophilic groups. In some examples, the monovinyl aromatic monomers used to prepare the macroporous copolymer may include styrene and its derivatives, for example, α-methylstyrene, vinyl toluene, vinyl naphthalene, vinylbenzyl chloride, and vinylbenzyl alcohol. An example macroporous copolymer that may be used is Dowex SD2 (Dow Chemical Company, Midland, Mich.), which is FDA-approved as a food additive. Dowex SD2, and other suitable macroporous copolymers, are described in U.S. Pat. No. 4,950,332, which is incorporated herein in its entirety by reference. Dowex SD2 exhibits little to no swelling, leading to better operability. Adsorbent resin 22 may adsorb contaminants such as riboflavin, proteins, and Maillard reaction products to purify lactose in clarified stream 16. Thus, apart from decolorizing, adsorbent resin 22 may also increase the purity of lactose obtained in decolorized stream 28.
In some examples, adsorbent resin 22 resin may be periodically desorbed or regenerated, as described below. Adsorption system 20 discharges a decolorized stream 28 including a lactose solution of a higher purity (for example, having a lower concentration of contaminants such as riboflavin, proteins, or other non-lactose components) compared to lactose in clarified stream 16.
Decolorized stream 28 may be further processed to crystallize and extract lactose crystals, to ultimately form lactose powder of a predetermined purity. In some examples, system 10 may include a crystallization system 38. Crystallization system 38 receives decolorized stream 28, and crystallizes crystals of purified lactose from decolorized stream 28 to generate a slurry stream 40 including lactose crystals suspended in an aqueous medium. Crystallization system 38 may include, for example, one or more evaporators that concentrate the lactose solution by removing water, and cool and agitate the concentrated lactose solution to initiate lactose crystal formation and uniform growth. In some examples, crystallization system 38 may include a series of crystallization stages including evaporators having agitators for concentrating and crystallizing lactose crystals from decolorized stream 28 to form slurry stream 40. Slurry stream 40 may include a cake, slurry, or paste of lactose crystals.
In some examples, system 10 may include a crystal separation system 42, which receives slurry stream 40, and separates lactose crystals in slurry stream 40 from the medium, to generate crystal stream 44. In some examples, crystal separation system 42 may include a decanter, a gravity settler, a centrifuge, a screen, a mesh, or other suitable apparatus for separating lactose crystals from the mother liquor in slurry stream 40.
In some examples, system 10 may include a drying system 46. Drying system 46 may receive slurry stream 40 or crystal stream 44, and dries lactose crystals in slurry stream 40 or crystal stream 44 to a predetermined dryness, to generate dry lactose stream 48. Drying system 46 may be configured to dry lactose crystals in slurry stream 40 or crystal stream 44 into a friable material. Drying system 46 may be configured to dry lactose crystals by removing additional water so that dry lactose stream 48 that exits the drying system 46 has a solids content of at least about 92 wt. % TS, such as at least about 94 wt. % TS, for example at least about 94.9 wt. % TS. Lactose produced by crystallization contains 5.00% water of hydration. Therefore, a dried lactose product will preferably contain less than 0.1% free moisture to prevent caking and molding in storage. Drying system 46 may include, for example, an oven, a spray dryer, a drum dryer, or a fluidized bed dryer. The dry lactose stream 48 may further be subjected to milling or other granulation processes to arrive at a predetermined particle size and distribution of lactose. Drying system 46 may also include a dryer capable of removing virtually all of the water of hydration to produce anhydrous lactose. Alternatively, the product stream 28 can be crystallized and dried at a temperature above 93.5° C. to produce beta-lactose rather than alpha-lactose monohydrate.
Thus, system 10 may be used to purify relatively low-grade lactose (such as edible grade lactose) in supply stream 12 to a predetermined purity, for example, a pharmaceutical-grade lactose product. In some examples, the pharmaceutical-grade lactose product may have less than 5.1% by weight of water, less than 0.1% sulphated ash, and less than about 5 μg/g of heavy metals. Protein and light-absorbing impurities may be less than an amount exhibiting an absorbance of less than 0.27 at 210-220 nm, and less than 0.07 at 270-300 nm. In some examples, the lactose product according to the disclosure may include lactose monohydrate, for example, crystalline α-lactose monohydrate. In some examples, the lactose product may include no more than 0.1 by weight % residue on ignition, no more than 5 μg/g of heavy metals, no more than 0.04 absorbance per path length in cm at a wavelength of 400 nm.
In some embodiments, the process of
In some embodiments, the example technique of
The example technique of
In some examples, the example technique of
The example technique further includes mixing clarified stream 16 with adsorbent resin 22, for example, by passing clarified stream 16 through adsorption system 20 comprising adsorbent resin 22. The mixing decolorizes clarified stream 16 to produce decolorized stream 28 (56). In some examples, adsorbent resin 22 may be arranged in a packed bed. Clarified stream 16 may be pumped across a packed bed of resin 22 of adsorption system 20 at a predetermined volumetric flow rate. For example, clarified stream 16 may be pumped at a rate of about 15 bed volume/hour. In some examples, clarified stream 16 is loaded onto adsorbent resin 22 at a rate between about 4 and about 20 bed volumes per hour. The temperature of clarified stream 16 may be maintained at a temperature high enough to maintain all lactose in solution; typically, between about 60 and about 100° C., for example, at 77° C. As described with reference to
As adsorbent resin 22 commences to absorb riboflavin and other contaminants, its capacity to remove contaminants from clarified stream 16 may decrease to unacceptably low levels. For example, adsorbent resin 22 should typically remove all color, for example, yellow color, so that decolorized stream 28 is substantially or completely clear or transparent. As the capacity of adsorbent resin 22 declines, for example, as the resin approaches saturation, stream 28 may begin exhibiting a color, for example, a yellow color from increasing riboflavin concentration. Yellow color associated with riboflavin may be detected using a spectrophotometer, to measure absorption at a wavelength between 400 to 465 nm, for example, at 450 nm. Collection of the effluent may be paused or stopped when decolorized stream 28 exhibits a yellow color. Adsorbent resin 22 may be periodically washed, replaced, refreshed, or regenerated. In some examples, collection of effluent may be stopped after about 10 bed volumes. In some examples, the flow rate of clarified stream 16 may be set so that adsorbent resin 22 needs to be washed only once in a production period or production shift, for example, once every day, or once every 12 hours, or any other suitable period. A regeneration regimen may include treating the resin bed with a solution or series of solutions including agents such as dilute caustic, dilute acid, NaCl, and hot water.
The amount of adsorbent resin 22, for example, the ratio of weight of processed lactose to the weight of resin depends on the source of the lactose. All other parameters remaining the same, a lactose source containing a higher proportion of riboflavin will entail the use of a higher amount of resin. The dimensions of adsorbent resin 22, for example in a packed bed, depend on linear flow rate, solution viscosity, and resin parameters. While the example technique of
In some examples, the example technique of
In some examples, the example technique of
In some examples, the example technique of
In some examples, the example technique of
The example technique of
Various examples of the invention have been described. These and other examples are within the scope of the following claims.
This application is a national stage entry under 35 U.S.C. § 371 of PCT Application No. PCT/US2017/056334, filed Oct. 12, 2017, which claims the benefit of U.S. Provisional Patent Application Ser. No. 62/408,580, titled “HIGH PURITY LACTOSE,” which was filed on Oct. 14, 2016. The entire contents of PCT Application No. PCT/US2017/056334 and U.S. Provisional Patent Application Ser. No. 62/408,580 are incorporated herein by reference.
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| PCT/US2017/056334 | 10/12/2017 | WO |
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| WO2018/071665 | 4/19/2018 | WO | A |
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| Number | Date | Country | |
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| 20200190608 A1 | Jun 2020 | US |
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| 62408580 | Oct 2016 | US |
