WO2022026431A1

WO2022026431A1 - Multistage agitation for the crystallization of spray dried or amorphous solid materials

Info

Publication number: WO2022026431A1
Application number: PCT/US2021/043259
Authority: WO
Inventors: Nan QI
Original assignee: Corn Products Development, Inc.
Priority date: 2020-07-29
Filing date: 2021-07-27
Publication date: 2022-02-03

Abstract

A method using an increase of agitation energy per unit volume in the crystallization of amorphous solid or spray dried solid starting material is provided. This method improves the efficiency of crystallization process and corresponding subsequent processes. Among the improvements associated with various embodiments are increased productivities and decreased process times in crystallization, centrifugation, filtration, and solid drying processes; increased product recovery; maintenance of the similar, or increased, product yield; maintenance of the similar, or increased, product purity; and potential elimination of dry milling the crystal products.

Description

Multistage Agitation for the Crystallization of Spray Dried or Amorphous Solid Materials

[0001] This application claims priority under 35 U.S.C. § 119 to Provisional Application U.S. Serial No. 63/057,973, filed on July 29, 2020, which is hereby incorporated herein by reference in its entirety.

[0002] The present invention relates to crystallization processes.

[0003] In industry, crystallization is an important separation and purification process that can be used to make crystalline products. These crystalline products can be incorporated into end-products that are manufactured in the food and beverage industry, in the pharmaceutical industry, and in the cosmetics industry, as well as in many other industries.

[0004] Crystallization processes usually include the combination of a starting material with a solvent, agitation to complete dissolution, generation of a supersaturated solution, seeding, growth, and subsequent solid-liquid separation. Examples of means for solid-liquid separation include, but are not limited to, filtration and centrifugation and combinations thereof.

[0005] When developing a crystallization process, one must be mindful that in addition to product purity, one needs to consider crystal particle size distribution, crystal form, and crystal morphology because each of these parameters can affect downstream processes. In many commonly employed practices for the crystallization of starting materials, such as spray dried or amorphous solids, a single agitation pattern is employed. When performing agitation in these systems, often the agitation energy per unit volume is provided at a low level and agitation is applied intermittently. Consequently, it is not uncommon in industrial practices to spend an undesirably long time, for example, approximately sixty hours, in a crystallization process. These long crystallization processes often correspond to low productivity. Additionally, subsequent processes such as filtration, centrifugation, and solid drying that follow a crystallization process using intermittent agitation can also require unacceptably long process time periods.

[0006] In other industrial practices, continuous agitation is applied at, for example, high agitation energy per unit volume. However, processes for crystallization of spray dried or amorphous solids to which continuous constant agitation at high agitation energy per unit volume is applied can also lead to undesirable results, for example, the particle sizes of crystals in the crystallization end slurry can be too small. This in turn can cause subsequent filtration, centrifugation, and solid drying to take unacceptably long time periods. Additionally, the product yield may be reduced due to the loss of fine product solids during centrifugation and/or filtration.

[0007] Therefore, there is a need to develop new and effective agitation strategies in processes that involve the crystallization of spray dried or amorphous solid materials. When addressing this need, one should consider one or more of the product and process characteristics such as product yield, product recovery, product purity, process time taken, and energy consumed.

[0008] The present invention provides methods for crystallizing starting materials that may, for example, be spray dried or amorphous solids. Using various embodiments of the present invention, one may efficiently and effectively obtain the desired crystalline products, which also may be referred to as crystallized products, crystal products, or crystallization products. By way of a non-limiting example, a crystalline product that is obtained according to the present invention may be used as a sole ingredient or one of a number of ingredients in sweetener products, food and beverage products, cosmetic products, pharmaceutical products, chemical products, and other products.

[0009] In some embodiments, the present invention provides a method for making a crystallized product. The method comprises: (a) exposing a crystallization mixture material to a selected agitation energy per unit volume, wherein the crystallization mixture material comprises a solvent and chemical compounds, wherein the chemical compounds are obtained by dissolving an amorphous solid starting material or a spray dried solid starting material in the solvent; (b) after (a), exposing the crystallization mixture material to a higher agitation energy per unit volume, wherein the higher agitation energy per unit volume is greater than the selected agitation energy per unit volume; and (c) after (b), obtaining a crystallized product, wherein the crystallized product comprises one or more crystals.

[0010] In some embodiments, the present invention is directed to a method for making a crystallized product comprising the steps of: (a) applying intermittent agitation to a crystallization initial solution for a first period of time to form a crystallization mixture material, wherein during the first period of time, the crystallization initial solution is exposed to a first agitation energy per unit volume and the crystallization initial solution comprises chemical compounds from an amorphous solid starting material or a spray dried solid starting material that has been dissolved in a solvent; (b) applying a first continuous agitation for a second period of time, wherein the second period of time is after the first period of time and during the second period of time, the crystallization mixture material is exposed to a second agitation energy per unit volume, wherein the second agitation energy per unit volume is greater than the first agitation energy per unit volume; (c) applying a second continuous agitation for a third period of time, wherein the third period of time is after the second period of time and during the third period of time, the crystallization mixture material is exposed to a third agitation energy per unit volume, wherein the third agitation energy per unit volume is greater than the second agitation energy per unit volume; and (d) obtaining a crystallized product after the third period of time, wherein the crystallized product comprises one or more crystals.

[0011] Through various embodiments of the present invention, one may obtain one or more of the following benefits: reduced process time and increased process productivity in crystallization; increased solid product yield; increased recoveries of the desired compounds in the solid product; reduced process time and increased process productivity in subsequent solid-liquid separation such as filtration and/or centrifugation; reduced process time and increased process productivity in subsequent solid product drying; reduced agglomeration of solid products; reduced process time and increased process productivity in subsequent dry milling of dry solid products; and total elimination of the need for subsequent dry milling of dry solid products.

Brief Description of the Figures

[0012] Figure 1 is a process flow diagram that is a representation of a method of the present invention.

[0013] Figure 2 is a process flow diagram that is a representation of the process steps of figure 1 with step 2 broken into stages 2.1, 2.2, and 2.3.

[0014] Figures 3A-3D are graphs that illustrate agitation speed relative to time for step 1 (figure 3A), step 2/stage 2.1 (figure 3B), step 2/stage 2.2 (figure 3C), and step 2/stage 2.3 (figure 3D) of a method of the present invention. [0015] Reference will now be made in detail to various embodiments of the present invention, examples of which are illustrated in the accompanying figures. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, unless otherwise indicated or implicit from context, the details are intended to be examples and should not be deemed to limit the scope of the invention in any way. Additionally, features described in connection with the various or specific embodiments are not to be construed as not appropriate for use in connection with other embodiments disclosed herein unless such exclusivity is explicitly stated or implicit from context. Further, headers are provided for the convenience of the reader and do not limit the scope of any of the embodiments described herein.

Multistage Agitation

[0016] Certain embodiments of the present invention are directed to methods that comprise, consist essentially of, or consist of two or more stages of agitation ( e.g ., 2 to 20 stages or 4 to 10 stages) in which there is an increase in agitation energy per unit volume as the process moves from one stage to the next stage. When there are two stages of agitation, the stages may be referred to as a first stage and a second stage with the second stage coming after the first stage. Thus, one may, for example, increase the motion of liquid or slurry of a crystallization mixture material. A “crystallization mixture material” is a combination of a solvent, chemical compounds and substances to which a crystallization process or portions of a crystallization process will be applied. It may, for example, comprise, consist essentially of, or consist of a solvent and the chemical compounds that have been obtained from a spray dried solid starting material or an amorphous solid starting material that is initially dissolved in that solvent in the beginning of a crystallization process. Thus, when a spray dried solid starting material or an amorphous solid starting material is completely dissolved in a solution, the chemical compounds that made up the spray dried solid starting material or the amorphous solid starting material will be the chemical compounds within the solution.

[0017] As the crystallization mixture material moves to a subsequent stage of crystallization, the agitation energy per unit volume is increased. Thus, in a process of the present invention, the crystallization mixture material may be exposed to a selected agitation energy per unit volume and then to a higher agitation energy per unit volume. These two stages may be discrete, and the transition may occur as a step change or may be continuous. Further, there may be two or more stages of increase in agitation energy per unit volume in a crystallization process, for example 2 to 20 stages or 3 to 10 stages or 3 to 5 stages.

[0018] The term “higher” is used relative to the term “selected” to indicate that there is an increase of agitation energy per unit volume following the exposure of the selected agitation energy per unit volume. Additionally, in some embodiments, there may be exposure to no other agitation energy per unit volume before and/or after these two stages of agitation, or there may be exposure to one or more agitation energies per unit volume before and/or after these two stages of agitation.

[0019] In some embodiments, the present invention comprises, consists essentially of, or consists of three stages of agitation: (a) an intermittent agitation; (b) a first continuous agitation; and (c) a second continuous agitation. In some embodiments, the complete process of these three stages of agitation is conducted in under 30 hours, e.g., 1 hour to 20 hours or 5 hours to 25 hours. The three stages of agitation may be performed in the same or different crystallizers, and there may or may not be a break in time between two agitation stages. Examples of crystallizers include, but are not limited to, stirred vessel crystallizers, fluidized bed crystallizers, tapered fluidized crystallizers, crystallizers with draft tube baffle designs, and crystallizers with oscillatory baffle designs. Further, within systems that are used to implement the present invention, agitators may have one or more impellers, e.g., a radial impeller or an axial flow impeller, or a combination thereof.

[0020] In some embodiments, the combination of the aforementioned three stages of agitation are part of a larger process. One of these processes is represented by the process flow diagram of figure 1. As shown in figure 1, one begins with a starting material 110 and a solvent 120. The starting material may be a liquid or a solid or a combination thereof. In some embodiments, it is a feed material, which may also be referred to as a raw material. In some embodiments, the starting material comprises, consists essentially of, or consists of an amorphous solid starting material, a spray dried solid starting material or a combination thereof.

[0021] As shown in figure 1, the starting material is dissolved in the solvent by mixing at step 1 132 to form a crystallization mixture material. Right after the full dissolution achieved and before step 2 136, the crystallization mixture material may also be referred to as a crystallization initial solution 134. The crystallization initial solution is preferably homogenous and is to what the multistage agitation of the present invention may be applied in what is denoted as step 2 136. In figure 1, 132, 134, and 136 collectively represent the crystallization process 130. In some embodiments, the crystallization initial solution is subjected to a filtration process to remove any insoluble impurities and particles before the start of the intermittent agitation.

[0022] After crystallization 130, in step 3 150, a crystallization end slurry 140 that has been formed is subjected to filtration or/and centrifugation to isolate the solid crystal product out of the mother liquor 170. The isolated solid crystal product forms a wet cake 160.

[0023] The wet cake 160 enters step 4 162, which corresponds to solid drying, to form a dry crystal product 164. The mother liquor 170 enters step 5 172, which is a spray drying process, to form a by-product solid 174. Although the solid drying step 162 and the spray drying step 172 are denoted by step 4 and step 5 respectively, the process may be designed so that they occur at the same time or at different times with either occurring before the other. Alternatively, the process may be designed to enter only one or the other of step 4 and step 5.

Before Intermittent Agitation

[0024] As shown in figure 2, in various embodiments of the present invention, the starting material is dissolved 132 in a solvent prior to the intermittent agitation. (Further, although figure 2 shows stage 2.1 for intermittent agitation, in some embodiment, this intermittent agitation stage may be omitted.) Examples of solvents that one may use in connection with the present invention include but are not limited to water, methanol, ethanol, propanol, acetone, acetic acid, acetonitrile, tetrahydrofuran, pyridine, methyl acetate, ethyl acetate, methylene chloride, ethyl ether, chloroform, dioxane, carbon tetra-chloride, toluene, benzene, and cyclohexane, as well as combinations thereof. In some embodiments, dissolving of the starting material in a solvent is performed at 20 °C to 70 °C, or exclusively at room temperature, e.g., 20 °C to 30 °C. [0025] Prior to the intermittent agitation, the initial combination of the starting material and the solvent may be agitated in order to dissolve 132 the starting material quickly and fully in that solvent. The agitation used here for dissolving may be continuous and at high agitation energy per unit volume, e.g., 40 to 400 rpm for a 2,000 liter to 10,000 liter crystallizer. After the starting material is fully dissolved, a crystallization initial solution is obtained. Other methods for forming crystallization initial solutions that are now known or that come to be known may be used in connection with the present invention.

[0026] In some embodiments, the crystallization initial solution is homogenous. Additionally, in some embodiments, it is a supersaturated solution. This crystallization initial solution comprises both the chemical compounds that have been dissolved from the starting material and the solvent.

[0027] During or prior to stage 2.1, one may add a seed to facilitate crystallization. After seeding, optionally, continuous agitation can be provided at a medium or high agitation (rpm) for a short period of time, e.g., 0.1 to 15 minutes in order to distribute the seed evenly.

[0028] When using a seed, one may add a certain amount of crystals that are the same as or different from the crystallized product in a previous batch from the same starting material and the same process. Seeding may have a significant benefit on both the chemical attributes (such as purity) and the physical attributes (such as crystal form, morphology, and particle size distribution) of a crystal product. For example, seed facilitates growth over nucleation and provides sufficient surface area for growth so that supersaturation may be released in a controlled manner. Persons of ordinary skill in the art are familiar with how to use seeds in crystallization processes.

[0029] The seed may be added as a dry solid or a pre-made slurry. In some embodiments, when seeding, all of the seed material is added at one time and while or before the crystallization initial solution is under agitation at a medium to high speed. By way of a non-limiting example, one may add a small amount of high purity rebaudioside(s) as seed in an amount that is 1.0% - 10.0 wt.% of the weight of the starting material. The seed may be added to the crystallization initial solution at any time prior to the initiation of the intermittent agitation.

Intermittent Agitation [0030] Similar to figure 1, figure 2 provides a process flow diagram of various embodiments of the present invention. However, in figure 2, the five process steps referenced in figure 1 are identified with step 2 broken into three sub-stages: stage 2.1, stage 2.2, and stage 2.3. Following step 1 132 to obtain the crystallization initial solution, the process enters an intermittent agitation stage 2.1. The phrase “intermittent agitation” means two or more periods of continuous agitation, each of which is separated from the next period of continuous agitation by a time period during which there is no agitation. Thus, between consecutive continuous agitations within stage 2.1, there is a time interval during which no agitation occurs. The intermittent agitation may be at regular intervals (i.e. having the same amount of time of no agitation between two consecutive continuous agitations and optionally at the same agitation durations and at the same agitation speed during agitation) and may be referred to as cyclic; or at irregular intervals and may be referred to as periodic. Regardless of whether the periods of no agitation are of uniform intervals, during the entire intermittent agitation stage, there are a plurality of discrete periods of continuous agitation. Figure 2 shows a single period of intermittent agitation; however, within the scope of the present invention there may be the use of a plurality of periods of intermittent agitation with each period of intermittent agitation having a higher agitation energy per unit volume than the period of intermittent agitation that precedes it. When there is a plurality of periods of intermittent agitation ( e.g 2 to 20 or 4 to 10), in some embodiments, all of the periods of intermittent agitation precede the periods of continuous agitation described herein.

[0031] The duration of the entire intermittent agitation stage may be referred to as the first period of time. In some embodiments, the first period of time is from 0.1 to 200 hours, or from 0.5 hours to 60 hours, or from 1 hour to 30 hours, or from 1 hour to 25 hours, or from 5 hours to 20 hours, or from 10 hours to 15 hours.

[0032] In some embodiments, each period of agitation during the first period of time for intermittent agitation lasts from 10 seconds to 30 minutes or 30 seconds to 15 minutes and there are intervals of from 1 minute to 10 hours or 10 minutes to 4 hours without agitation between two consecutive continuous agitations. The duration of each continuous agitation may be the same or two or more of them may be different or each of them may be different. In some embodiments, during the intermittent agitation stage (i.e., the first period of time), the total amount of time for continuous agitations takes less than 80%, less than 40%, less than 20%, less than 5%, less than 2%, less than 0.5%, or less than 0.1% of the time.

[0033] In some embodiments, the intermittent agitation is at 10 to 200 rpm for a 2000 to 3000 liter crystallizer. Among the plurality of agitations during stage 2.1 220, the agitation speeds may be the same or different. Examples of agitation speeds are 0.5 to 500 rpm, or 25 to 200 rpm, or 50 to 100 rpm.

Continuous Agitation

[0034] Following the intermittent agitation stage, there are two or more periods of continuous agitation e.g., 2 to 20 or 4 to 10. When there are two stages of continuous agitation, there may be a first continuous agitation stage denoted as stage 2.2230 and a second continuous agitation stage, denoted as stage 2.3 240. Optionally, there is a break between only the intermittent agitation and the first continuous agitation stage or there is a break between only the first continuous agitation stage and the second continuous agitation stage, or there is a break in agitation during both transitions or there is no break during either transition. In some embodiments, there is an abrupt or a stepwise increase in agitation energy per unit volume between the first continuous agitation stage and the second continuous agitation stage. In other embodiments, the increase of agitation energy per unit volume is not stepwise, and may, for example, be continuous, linear or exponential or otherwise, regular or irregular, or a combination thereof.

[0035] In some embodiments, the first continuous agitation stage is at 0.5 to 500 rpm, or 1 to 200 rpm, or 10 to 100 rpm, or 25 to 100 rpm, for 0.2 minutes to 200 hours, or 10 minutes to 50 hours, or 0.5 hours to 15 hours, or 0.5 hours to 5 hours. In some embodiments, the second continuous agitation is at 10 to 500 rpm, or 25 to 200 rpm, or 40 to 150 rpm, for 0.2 minutes to 250 hours, or 1 minutes to 100 hours, or 10 minutes to 80 hours, or 1 hour to 40 hours, or 5 hours to 20 hours. During either or both of the first continuous agitation stage and the second continuous agitation stage, the agitation energy per unit volume may be constant or vary. For example, during the first continuous agitation stage the agitation energy per unit volume may vary within a first range, and during the second continuous agitation stage the agitation energy per unit volume may vary within a second range. In some embodiments, the first range and the second range do not overlap. [0036] In some embodiments, between the first continuous agitation stage and the second continuous agitation stage, the agitation speed may be increased by at least 1%, at least 5%, at least 10%, at least 50%, at least 100%, at least 200%, at least 300%, or at least 400%. Thus, for example, during the second continuous agitation stage, a crystallizer may be agitated at least 1% greater in rpm than the crystallizer is agitated during the first continuous agitation stage. If the agitation speed is not constant within either or both of the first continuous agitation stage and the second continuous agitation stage, the agitation speed increase may be referred to as the increase of the averaged agitation speeds during each continuous agitation stage. Alternatively, if the agitation speed is not constant within either or both of the first continuous agitation stage and the second continuous agitation stage, the agitation speed increase may refer to as the increase of the minimum agitation speeds or the increase of the maximum agitation speeds during each stage.

[0037] The duration of the first continuous agitation stage may be referred to as a second period of time, and the duration of the second continuous agitation may be referred to as a third period of time. In some embodiments, the third period of time is greater than the second period of time, e.g., at least 1% greater, at least 5% greater, at least 20% greater, at least 50% greater, at least 100% greater, at least 300% greater, or at least 600% greater.

[0038] In some embodiments, during the second continuous agitation, a crystallizer is agitated at least 1% greater in time than the crystallizer is agitated during the first continuous agitation.

Recovery of Crystallized Materials

[0039] At the end of the last continuous agitation stage, e.g., the second continuous agitation stage 2.3 240, a crystallization end slurry 140 is obtained. Next, as denoted in step 3 150, the crystallized solid product is separated out from the mother liquor. Separation may, for example, be accomplished by filtration or centrifugation or a combination thereof. By way of a non-limiting example, filtration may include washing with a solvent to remove residue impurities left in the wet cake.

[0040] As shown in figure 2, one or both of step 4 and step 5 may be entered. Step 4 162 refers to drying the wet cake to form a dry crystal product. Step 5 172 refers to spray drying the mother liquor to form a by-product solid. Starting Materials

[0041] The multistage agitation of the present invention may be applied to a crystallization initial solution, which is obtained by dissolving a starting material with a solvent. By way of non-limiting examples, the starting material 110 may comprise, consist essentially of, or consist of a spray dried solid material or an amorphous solid material or a combination thereof.

[0042] Spray dried materials can be made with a spray dryer. Typically, in a spray drying process, a concentrated liquid stream is continuously fed to a spray dryer through a spray dry nozzle. The nozzle is also fed with an air stream, and the spray dry nozzle breaks the liquid into fine droplets, e.g., on the order of millions of droplets. The liquid droplets lose their liquid solvent quickly through evaporation during the process. Spray drying processes can proceed so quickly that molecules or atoms don’t have time to organize themselves into a highly ordered crystalline lattice structure. Consequently, a spray dried solid material is often an amorphous solid.

[0043] An amorphous solid, which may or may not be obtained from the spray drying process, is a non-crystalline solid. Herein, “amorphous” describes a solid state in which molecules or atoms are not arranged in a strict order as in a definite crystalline lattice pattern. Amorphous solids often have higher solubilities than their crystalline solid counterparts, despite both having the same chemical composition. The difference between the spatial arrangement of the molecules or atoms in amorphous solids and their crystalline solid counterparts causes the difference in solubility between these two solids. Crystallization is a process utilizing solubility changes or differences to purify materials by growing crystals at high purity.

[0044] The present invention is not limited to the starting materials of any particular chemical composition. In some embodiments, the starting materials are raw materials in their initial states. In other embodiments, the starting materials have been processed to some degree or the starting materials are the remaining materials after some amount of compounds or materials are separated out through previous processes. Further, although the figures show “step 1” as dissolving a starting material in a solvent, the various embodiments of the present invention do not require this step when one already has a crystallization initial solution, i.e., a mixture solution in which a starting material has already been dissolved in a solvent.

[0045] In one embodiment, the starting material comprises, consists essentially of, consists of, or is derived from a stevia extract. The stevia extract may be obtained directly from a Stevia rebaudiana plant or after some processing of the plant. Technologies for obtaining stevia extracts are well-known to persons of ordinary skill in the art. For example, one may extract diterpene glycosides from stevia leaves using water or water-alcohol mixture solvents. In some embodiments, the starting material comprises a stevia extract, or a remaining stevia extract after a significant amount of steviol glycosides are separated out from the original crude stevia extract through previous separation processes.

[0046] By way of non-limiting examples, the stevia extract that forms or from which the starting materials are obtained may have a total steviol glycoside content (TSG%) in an amount of 45 wt.% to 94 wt.%, or 60 wt.% to 80 wt.%. This is on a dry weight basis. In some embodiments, the starting materials contain impurities at levels of 5 wt.% to 55 wt.%, or 5 wt.% to 30 wt.%, or 30 wt.% to 55 wt.%.

[0047] Within the starting material, the stevia extract may, e.g., comprise Reb A. The Reb A may, for example, be present at an amount of 20 wt.% to 85 wt.% of the total steviol glycoside content.

[0048] Additionally or alternatively, the starting material may comprise at least one of Reb B, Reb C, Reb D, Reb F, dulcoside A, rubusoside, stevioside, steviolbioside; a plurality of Reb B, Reb C, Reb D, Reb F, dulcoside A, rubusoside, stevioside, steviolbiosde; or all of Reb B, Reb C, Reb D, Reb F, dulcoside A, rubusoside, stevioside, steviolbioside. By way of non-limiting examples, when present, any or each of these materials may, for example, be present at the following amounts: Reb B: 0.5 wt.% to 5.0 wt.%; Reb C: 4.0 wt.% to 8.5 wt.%; Reb D: 1.5 wt.% to 3.0 wt.%;

Reb F: 0.5 wt.% to 2.0 wt.%; dulcoside A: 0.1 wt.% to 4.0 wt.%; rubusoside: 0.5 wt.% to 14.0 wt.%; stevioside: 5.0 wt.% to 16.0 wt.%; and steviolbioside: 0.1 wt.% to 1.0 wt.%.

Agitation Energy Per Unit Volume

[0049] The multiple stages of agitation of the present invention may be described using agitation energy per unit volume. As persons of ordinary skill in the art are aware of, agitation energy per unit volume is the energy consumption of the agitator shaft used to agitate a unit volume of liquid or a slurry. For the same crystallizer, agitator and liquid or slurry system, agitation energy per unit volume can be a reflection of the combination of the speed of agitation ( e.g in rpm), the time period of agitation, and the frequency of agitation if the agitation is intermittent (how often the agitation is provided). Thus, when one refers to a higher agitation energy per unit volume during a time period as opposed to another time period, one means the total agitation energy per unit volume during that time period is greater than during the other time period. Further, when referring to an amount of agitation power per unit volume during a time period, one may be referring to a uniform or non-uniform rate of agitation power consumption.

[0050] Figures 3A-3D illustrate how agitation energy per unit volume during different process steps and stages may compare in various embodiments of present invention. Figure 3A depicts the agitation during step 1 132 as shown in figures 1 and 2. Step 1 132 is the dissolving step in which the starting material is dissolved in a solvent by agitation so as to obtain the crystallization initial solution. The X-axis depicts time (to dissolve) and the Y-axis depicts agitation speed in rpm (revolutions per minute). The shaded area corresponds to when agitation is occurring during a time period t dissolve. If the rpms are constant at r dissolve for a crystallizer with fixed dimensions, the agitation energy per unit volume during t_dissolve is proportional to (r_dissolve)³ x (t_dissolve) in turbulent flow, and proportional to (r_dissolve)^{2 c} (t_dissolve) in laminar flow.

[0051] In some embodiments, the starting material is amorphous and highly soluble. In some embodiments, agitation for dissolving during step 1 132 may be performed until the starting material is fully dissolved, but then stopped as soon as the full dissolution is reached.

[0052] When using certain starting materials such as stevia extracts, one may be able to obtain crystallization initial solutions that are not only homogenous mixtures, but also are supersaturated. In these circumstances, preferably, one enters step 2 136 as soon as one completes step 1 132 or within a short time e.g., less than 5 minutes, after one completes step 1 132.

[0053] The intermittent agitation stage 2.1 (220 in figure 2) in step 2 136 is depicted in figure 3B. The entire duration of intermittent agitation is denoted as U. Each of the pulse agitation periods (ti, t2, and t3) includes a continuous agitation time period followed by a time period in which there is no agitation. The speed of agitation is represented by n. In figure 3B, for illustrative purposes, ri is shown as a constant across all continuous agitation time periods within U. However, n for each of the continuous agitation time periods can be the same or different, and n within any continuous agitation time period can be constant or varying. In figure 3B, within U, there are four continuous agitation time periods. However, this number (four) of continuous agitation time periods is for illustrative purposes, and there can be fewer or a greater numbers of continuous agitation time periods during stage 2.1 (figure 3B), e.g., 2 to 50 or 4 to 40 or 5 to 25.

[0054] The denotation of tm refers to the time length of any continuous agitation time period within an intermittent agitation stage 2.1 (figure 3B).

[0055] The continuous agitation time period for each pulse agitation period (e.g., ti, t2, t3) can be the same or different. Additionally, any two or more of these continuous agitation time periods can be the same or different. Finally, n can be the same as, greater than, or less than r_dissolve shown in figure 3A. For a crystallizer with fixed dimensions, the corresponding total agitation energy per unit volume during stage 2.1 is proportional to

in turbulent flow, and proportional to åf=i(^ri ^x T ) in laminar flow, wherein i represents the /th continuous agitation time period and there are total n of such continuous agitation time periods in stage 2 1

[0056] Following the intermittent agitation, the process enters the first continuous agitation stage (stage 2.2230 in figure 2), which corresponds to the graph shown in figure 3C. In figure 3C, the shaded area represents a continuous agitation that lasts until a time t_x. During stage 2.2, if the rpm is constant at n for a crystallizer with fixed dimensions, the corresponding agitation energy per unit volume during tx is proportional to (n)^{3 c} tx in turbulent flow, and proportional to (n)^{2 c} t_x in laminar flow. This first continuous agitation stage 2.2 may come immediately after stage 2.1 or there may be a gap in time between the end of stage 2.1 and the start of stage 2.2. The agitation speed in stage 2.2 as shown in figure 3C is constant at n. The value of G2 may be greater than, less than, or the same as n and it may be constant or varying. Additionally, t_x may correspond to a time that is larger than, the same as, or smaller than U. The agitation in stage 2.2 is applied continuously, and the agitation energy per unit volume during stage 2.2 is larger than the total agitation energy per unit volume during stage 2.1.

[0057] Following the first continuous agitation stage 2.2230, the process enters the second continuous agitation stage 2.3 240. As shown in figure 3D, the second continuous agitation stage 2.3 lasts until a time of t_y. The value of t_y may be greater than or equal to the value of t_x. The agitation speed in figure 3D is denoted as n, and G3 may be greater than or equal to n. The agitation energy per unit volume over the second continuous agitation stage during t_y is proportional to (n)³ x t_y in turbulent flow, and proportional to (n)² x t_y in laminar flow. The agitation energy per unit volume during the second continuous agitation stage shown in figure 3D may be greater than the agitation energy per unit volume during the first continuous agitation stage shown in figure 3C. In some embodiments, the agitation energy per unit volume over the second time period (corresponding to the first continuous agitation stage) is greater than e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total agitation energy per unit volume over the first time period (corresponding to the intermittent agitation stage). Similarly, in some embodiments, the agitation energy per unit volume over the third time period (corresponding to the second continuous agitation stage) is greater than e.g., at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the agitation energy per unit volume of the second time period (corresponding to the first continuous agitation step).

[0058] Between the intermittent agitation stage and the first continuous agitation stage, there may be a short time period of no agitation (e.g., up to 5 minutes or up to 40 minutes) or no time periods in which there is an absence of agitation. Between the first continuous agitation stage and the second continuous agitation stage, there also may be a short period of no agitation (e.g., up to 5 minutes or up to 40 minutes) or an absence of time periods in which there is no agitation.

Temperature

[0059] The various embodiments of the present invention may be flexibly employed at temperatures that are currently being used for crystallization processes. Therefore, in some embodiments, the multistage agitations are carried out at ambient temperature. In other embodiments, during periods of multistage agitation of present invention, heat is introduced, thereby raising the temperature of the system or heat is removed, thereby lowering the temperature of the system.

[0060] Additionally, the temperature may be kept constant throughout the three agitation stages of the present invention or it may vary between any two or among all three agitation stages. Further, when the temperature varies, the variation may be regular or irregular and increase, decrease, or both increase and decrease within or between stages. For example, known techniques of temperature cycling may be employed.

Industrial Processes

[0061] The methods of the present invention may be used one or more times during the crystallization process of obtaining desirable crystal products.

[0062] For example, when making a sweetener product comprising purified steviol glycosides, one may follow the generally known process steps of:

1. First crystallization step:

Crude stevia extract - Reb A + First by-product liquid stream

2. Spray drying step:

First by-product liquid stream - Remaining stevia extract

3. Second crystallization step:

Remaining stevia extract - Purified steviol glycosides +

Second by-product liquid stream

4. Blending step:

Purified steviol glycosides + Reb A - Stevia sweetener product [0063] The methods of the present invention may be applied in either or both of the first and the second crystallization steps described in the preceding paragraph. Additionally, to obtain the purified steviol glycosides, after the second crystallization step but prior to the blending step, one may need to separate the crystal solids from liquids (mother liquor) through, for example, filtration, centrifugation or both, and may also need to dry the wet cake of purified steviol glycosides to obtain a dry crystal product. If the dry crystal product of purified steviol glycosides has undesirable levels of agglomeration, dry milling the dry crystal product will be performed to achieve the desired particle size distribution. Dried purified steviol glycosides are often blended with Reb A as shown in Step 4 of the preceding paragraph in order to reach different Reb A compositions in the final products to meet different customers’ needs. As the four steps above suggest, crystallization can be used to obtain single crystallized steviol glycoside compounds, e.g., Reb A as made in the first crystallization step, or to obtain a plurality of crystallized steviol glycosides as made in the second crystallization step.

[0064] Here, crystallized Reb A and purified steviol glycosides are used as examples of crystallization products from present invention. However, by selecting the starting materials, different solvents, and crystallization conditions, persons of ordinary skill in the art may apply the present invention to other crystallization processes to obtain crystallization products that comprise, consist essentially of, or consist of one or more of Reb B, Reb C, Reb D, Reb F, Reb M, dulcoside A, rubusoside, stevioside, and steviolbioside apart from or in addition to Reb A.

Uses

[0065] The crystallized products from the present invention may, for example, be used in food and beverage, cosmetic, pharmaceutical, or chemical applications. In some embodiments, one may create a food or beverage product through combining a crystallized product, which is obtained using one or more of the various embodiments of the present invention, with another ingredient. This combining may be through mixing, blending, dissolving or any other methods now known to persons of ordinary skill in the art or that come to be known in future. The food and beverage products, in which the crystallized products made from the present invention may be used include, but are not limited to, sweeteners and products that contain sweeteners.

[0066] Examples of food products, in which the crystallized products obtained through a method of the present invention may be used, include, but are not limited to, confections, condiments, chewing gum, frozen foods, canned foods, soy-based products, salad dressings, mayonnaise, vinegar, ice cream, cereal compositions, baked goods, dairy products such as yogurts, and tabletop sweetener compositions.

[0067] Examples of beverage products, in which the crystallized products obtained through a method of the present invention may be used, include, but are not limited to, ready-to-drink products that are carbonated (e.g., colas or other soft drinks, sparkling beverages, and malts) or non-carbonated (e.g., fruit juices, nectars, vegetable juices, sports drinks, energy drinks, enhanced water, coconut waters teas, coffees, cocoa drinks, beverages containing milk, beverages containing cereal extracts, smoothies, and alcoholic beverages), as well as powdered beverage products that are to be combined with a liquid base such as water, milk, or club soda.

[0068] The crystallized products that are obtained through the methods of the present invention may also be used in cosmetic compositions, dental compositions, pharmaceutical compositions and chemical compositions.

EXAMPLES

[0069] In all Examples 1, 2, and 3, the starting materials were spray dried “remaining stevia extracts” after significant amounts of Reb A were separated out from crude stevia extracts through the first crystallization as described in the second paragraph of the section above that is entitled Industrial Processes.

[0070] In all Examples 1, 2, and 3, “the second crystallization” process described in the second paragraph of the section above that is entitled Industrial Processes was performed on each starting material to obtain purified steviol glycosides with the product quality specification as greater than or equal to 95% TSG and greater than or equal to 50% Reb A.

Example 1

[0071] In Experiments 1 to 11, the same starting material comprising steviol glycosides (62.5% TSG, 24.4% Reb A, db) was subjected to 11 different agitation patterns, A to K, respectively during the crystallization. Here, “db” stands for on dry basis. In each of those experiments, 74.4 g of the starting material as dry solid and 165.7 g of methanol at 40 °C were added into a crystallizer. The solid was dissolved in the solvent under continuous agitation. Immediately after full dissolution was achieved, the agitation of patterns denoted in Table I was applied to the crystallization initial solution. The crystallization process was isothermal at 40 °C and included the addition of a seed.

[0072] After crystallization, dead end filtration was performed to isolate the product crystals of purified steviol glycosides from the mother liquor (i.e., the second by product liquid stream as denoted in the second paragraph of the section above that is entitled Industrial Processes.) The weight of filtrate that was collected and the time that was taken to filter for each filtration process were recorded. The filtration rate was calculated as the weight of filtrate that was collected divided by the filtration time. The wet cake of purified steviol glycosides was dried to the final product.

[0073] Table I provides a summary of the effects of the different agitation patterns on crystallization process time, filtration rate, product yield, and product purity.

[0074] The agitation pattern (A) provided to the crystallization initial solution in Experiment 1 was a 1 -stage cyclic agitation at 54 rpm for 1 minute every 4 hours, for a total of 60 hours. Thus, the total crystallization process time was 60 hours. This agitation pattern was a known process. The associated filtration rate, product yield, and product purity (TSG%, Reb A%, db) were acceptable. But the crystallization time, 60 hrs, was quite long and it corresponded with a process bottleneck. Example 1 was set as a baseline to which the agitation patterns of Experiments 2-11 were compared.

[0075] In Experiments 2-5, a 1-stage continuous agitation at constant agitation speed was provided for 60 hours to each crystallization initial solution. The continuous agitation speeds were 90, 160, 230, and 350 rpms, respectively. Compared to the results of Experiment 1, results of Experiments 2-5 were worse. The crystallization process times were the same (60 hours) but there were remarkable decreases in the filtration rate and the product purity (TSG% and Reb A%, db). The filtration rates, product yields and product purities of Experiments 2-5 were very similar to each other with a slight decreasing trend of filtrate rate corresponding to an increase of agitation speed in rpm.

[0076] In Experiments 6-8, a 1 -stage continuous agitation at constant agitation speed was provided for a shortened process time, only 20 hours, to each crystallization initial solution. The continuous agitation speeds were 160, 230, and 350 rpms, respectively. The shortened agitation time (20 hours) was applied in order to reduce possible crystal breakage, which was thought likely to be the cause for the decreases of filtration rates in Experiments 2-5 due to the long agitation time (60 hours). Compared to the results in Example 1, even at a short agitation time period, results from Experiments 6-8 were still unacceptable. There were remarkable decreases in filtration rate and product purity as of Reb A% db. Compared to Experiments 2-5, the filtrate rates from Experiments 6-8 were even smaller. This indicated that the low filtration rates in Examples 2-5 were not from crystal breakage due to long agitation time.

[0077] In Experiments 9-11, a 2-stage agitation pattern was developed and applied to each crystallization initial solution. The agitation patterns in Experiments 9-11 were of the present invention, and they were 1) a front cyclic agitation for 20 hours, followed by 2) a continuous agitation at constant agitation speed with higher agitation energy per unit volume of slurry, i.e., the agitation speed increased from 54 rpm (in the front cyclic agitation stage) to 230 rpm (in the following continuous agitation stage) and the continuous agitation time period increased from a total 5 of minutes (in the front cyclic agitation stage) to 5 hours (in Experiment 9), 20 hours (in Experiment 10) and 40 hours (in Experiment 11), respectively.

[0078] Compared to all 1 -stage continuous agitations at constant agitation speeds as in Experiments 2-8, the 2-stage agitation patterns of the present invention in Experiments 9-11 remarkably increased filtration rate and product purity (TSG% and Reb A%, db). Compared to the baseline case of 1 -stage cyclic agitation in Experiment 1, the 2-stage agitation patterns of the present invention in Experiments 9- 11 enabled the great reduction of crystallization process time from 60 hours to 25 hours (in Experiment 9) while still achieving similar filtration rates and product purities (TSG% and Reb A%, db). Data of Example 1 demonstrate that the 2-stage agitation patterns of the present invention are advantageous when compared to the 1- stage cyclic agitation pattern that is already known to persons of ordinary skill in the art, and it is much better than the 1 -stage continuous agitation patterns at the constant agitation speeds as normally seen in industrial practices. Thus, Example 1 demonstrates that the present invention can be used to make the same crystal product from spray dried or amorphous solid starting materials at an equivalent product purity level and filtration rate but in a much shortened crystallization process time.

Example 2

[0079] In large-scale Experiments 12 to 14, starting materials comprising steviol glycosides (71.3-77.0% TSG, 31.3-33.7% Reb A, db) were subjected to two different agitation patterns, A and L, respectively during crystallization. In these experiments, 722 kg of a starting material as dry solid and 1342 kg of methanol at 40 °C were added into a crystallizer. Except for the agitation pattern, the rest of crystallization process was the same as described in Example 1.

[0080] After crystallization, centrifugation was performed to separate the product crystals of purified steviol glycosides from the mother liquor. The wet cake of purified steviol glycosides was dried to final product. Table II summarizes the results. [0081] The baseline case agitation pattern (A) of a previously known technique was a 1-stage cyclic agitation. It was applied to Experiment 12. A 3-stage agitation pattern (L) with increasing agitation energy per unit volume was developed according to the present invention and was applied to Experiments 13 and 14. Experiment 14 was a repeat of Experiment 13. It can be seen that, compared to the 1 -stage cyclic agitation (A) of a prior art along with using high quality starting material (77.0% TSG and 33.7% Reb A, db) in Experiment 12, the 3-stage agitation pattern (L) of the present invention as in Experiments 13 and 14 allows one to achieve a similar product purity (TSG%, Reb A%, db) and product yield in much shortened process time in crystallization, i.e., from the original 60 hours down to 25 hours, and in equivalent process time in centrifugation with increased product recovery, i.e., from 47.2% for TSG and 61.4% for Reb A to 50.0-51.1% for TSG and 67.9-68.6% for Reb A, while using the starting materials even at lower quality (71.3-73.6% TSG and 31.3-32.4% Reb A, db). The results demonstrate that the present invention is a more efficient process for the crystallization of spray dried or amorphous solid materials than the 1- stage agitation as a commonly seen prior art.

Example 3

[0082] Additional large-scale experiments were performed using the starting materials comprising steviol glycosides (69.4-73.6% TSG, 30.4-32.1% Reb A, db) and the results are shown in Table III. Except for the agitation pattern, the rest of crystallization process and the subsequent centrifugation and solid drying were the same as described in Example 2. A baseline agitation pattern (A) of a known technique was a 1 -stage cyclic agitation. This baseline pattern (A) was applied to Experiment 15. The 3 -stage agitation pattern (L) of the present invention was applied to Experiment 16. Table III shows a comparison of crystallization rate, centrifugation rate, and drying rate for Experiments 15 and 16.

[0083] The data in Table III show that when the similar starting materials were processed with a multistage agitation strategy of the present invention in crystallization, production rates (i.e., productivities) in crystallization, centrifugation and solid drying processes were all improved. The dry milling process was required in Experiment 15 after the wet cake of crystal product was dried in order to reduce the agglomeration in dry product. However, dry milling process was eliminated after dried the wet crystal product, which was made in Experiment 16, due to the significant reduction of agglomeration in wet crystals. The multistage agitation of the present invention in crystallization eliminated the need of subsequent dry milling process. Using the multistage agitation of the present invention allowed the bottleneck to be shifted from crystallization (6.3 kg/hr) to drying process (8.4 kg/hr).

It debottlenecked the production in crystallization.

Claims

Claims We claim

1. A method for making a crystallized product, said method comprising:

(a) exposing a crystallization mixture material to a selected agitation energy per unit volume, wherein the crystallization mixture material comprises a solvent and chemical compounds, wherein the chemical compounds are obtained by dissolving an amorphous solid starting material or a spray dried solid starting material in the solvent;

(b) after (a), exposing the crystallization mixture material to a higher agitation energy per unit volume, wherein the higher agitation energy per unit volume is greater than the selected agitation energy per unit volume; and

(c) after (b), obtaining a crystallized product, wherein the crystallized product comprises one or more crystals.

2. The method according to claim 1, wherein the selected agitation energy per unit volume is applied through a first continuous agitation and the higher agitation energy per unit volume is applied through a second continuous agitation.

3. The method according to claim 2, wherein the first continuous agitation is at 1 to 200 rpm for 0.2 minutes to 200 hours.

4. The method according to either claim 2 or claim 3, wherein the second continuous agitation is at 10 to 500 rpm for 0.2 minutes to 200 hours.

5. The method according to any of claims 2 to 4, wherein during the second continuous agitation, a crystallizer is agitated at least 1% greater in rpm than said crystallizer is agitated during the first continuous agitation.

6. The method according to any of claims 2 to 5, wherein during the second continuous agitation, a crystallizer is agitated at least 1% greater in time than said crystallizer is agitated during the first continuous agitation.

7. The method according to any of claims 1 to 6, wherein said obtaining the crystallized product comprises a process for separating one or more solid crystal products from a mother liquor.

8. The method according to claim 7, wherein the process for separating solid products from the mother liquor comprises filtration.

9. The method according to claim 7 or claim 8, wherein the process for separating solid products from the mother liquor comprises centrifugation.

10. The method according to any of claims 1 to 9, wherein the selected agitation energy per unit volume is a second agitation energy per unit volume and the second agitation energy per unit volume is applied for a second period of time, and the higher agitation energy per unit volume is a third agitation energy per unit volume and the third agitation energy per unit is applied for a third period of time, and wherein prior to applying the second agitation energy per unit volume, the amorphous solid starting material or the spray dried solid starting material is dissolved in the solvent to form a crystallization initial solution and the method further comprises: applying intermittent agitation to the crystallization initial solution for a first period of time to form the crystallization mixture material, wherein during the first period of time, the crystallization initial solution is exposed to a first agitation energy per unit volume, and the second agitation energy per unit volume is greater than the first agitation energy per unit volume.

11. The method according to claim 10 further comprising subj ecting the crystallization initial solution to a filtration process to remove insoluble impurities and particles before the intermittent agitation.

12. The method according to claim 10 or claim 11, wherein the crystallization initial solution is a supersaturated solution.

13. The method according to any of claims 10 to 12, wherein the first period of time is from 0.1 to 200 hours.

14. The method according to any of claims 10 to 13, wherein the intermittent agitation comprises a plurality of periods of continuous agitation and a plurality of periods of an absence of agitation, wherein each period of continuous agitation in the first period of time has a duration of 10 seconds to 30 minutes.

15. The method according to any of claims 10 to 14 further comprising combining the crystallization initial solution with a seed prior to or while applying the intermittent agitation.

16. The method according to any of claims 10 to 15, wherein the amorphous solid starting material or the spray dried solid starting material comprises a stevia extract, or a remaining stevia extract after an amount of steviol glycosides has been separated out from an original crude stevia extract through a previous separation process.

17. The method according to claim 16, wherein the stevia extract or the remaining stevia extract has a total steviol glycoside content of 45 wt.% to 95 wt.% on a dry basis.

18. The method according to claim 16 or claim 17, wherein the stevia extract or the remaining stevia extract comprises Reb A.

19. The method according to claim 18, wherein the stevia extract or the remaining stevia extract further comprises at least one of Reb B, Reb C, Reb D, Reb F, dulcoside A, rubusoside, stevioside, steviolbioside, and Reb M.

20. The method according to claim 18 or claim 19, wherein of the total steviol glycoside content, 20 wt.% to 85 wt.% is Reb A.

21. The method according to any of claims 1 to 20, wherein the crystals comprise Reb A.

22. The method according to any of claims 1 to 21, wherein the crystals comprise Reb M.

23. A method of making a food or beverage product comprising the method of any of claims 1 to 22, and combining the crystallized product with an ingredient of a food or beverage product.