Use of lactate and amide as nucleating agents for poly(hydroxyalkanoate)s

Abstract

Described herein are orotate esters and amides as nucleating agents for crystallizing molten poly(hydroxyalkanoate)s. The orotate esters and amides are soluble in the molten poly(hydroxyalkanoate)s and have high nucleation efficiency. The use of the orotate esters and amides described herein provides several advantages with respect to producing articles composed of the poly(hydroxyalkanoate)s.

Description

Cross-Reference to Related Applications

[0001] This application claims the benefit and priority of co-pending U.S. Provisional Patent Application No. 63 / 569,788, filed March 26, 2024, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0002] Poly(hydroxyalkanoates) (PHAs) have a wide range of applications, and up to 100 different PHA structures have been identified. PHA structures can vary in two ways. For example, poly(hydroxybutyrate-co-hydroxyhexanoate) (PHBH) is a biodegradable copolymer of 3-hydroxybutyric acid (3HB) and 3-hydroxyhexanoic acid (3HHx) in the PHA family, exhibiting improved processability and material properties compared to its predecessor, poly(hydroxybutyrate) (PHB). 1 Despite the enormous potential of PHBH (and all other PHAs) as a means to offset the world’s dependence on single-use fossil fuels, their implementation has been slow: PHAs are hampered by their high production costs, significant physical aging, and poor crystallization kinetics. 2, 3 Although improvements in economies of scale have begun to reduce production costs, 4 Furthermore, advancements in formulation have begun to reduce the effects of physical aging. 5 However, PHA still faces challenges in terms of crystallization rate.

[0003] PHBH (and all other PHAs) are being considered for high-throughput, low-margin applications, such as single-use plastic products that require rapid manufacturing. 6 Therefore, long injection mold dwell times, slow production speeds, and long cycle times are contrary to industrial demands. Slow crystallization rates have traditionally been improved by adding small crystals to the polymer, which increase crystallization temperature and rate by providing nucleation sites that facilitate phase transitions at higher temperatures. 7, 8 Summary of the Invention

[0004] This article describes orotic esters and amides as nucleating agents for crystallizing molten poly(hydroxyalkanoates). The orotic esters and amides are soluble in the molten poly(hydroxyalkanoates) and exhibit high nucleation efficiency. Using the orotic esters and amides described herein provides several advantages for producing articles composed of the poly(hydroxyalkanoates).

[0005] Other compositions, apparatuses, methods, features, and advantages will become apparent to those skilled in the art upon examination of the following figures and detailed description. All such additional compositions, apparatuses, methods, features, and advantages are intended to be included within the scope of this disclosure and protected by the appended claims. Attached Figure Description

[0006] Further aspects of this disclosure will be more readily understood when the various embodiments described below are read in conjunction with the accompanying drawings.

[0007] Figures 1A-1D Non-isothermal differential scanning calorimetry (DSC) analysis of (a) methyl orotic acid, (b) ethyl orotic acid, (c) propyl orotic acid and (d) butyl orotic acid cooled at 10 °C / min in PHBH is shown.

[0008] Figures 2A-2D Non-isothermal differential scanning calorimetry (DSC) analysis of (a) methyl orotate, (b) ethyl orotate, (c) propyl orotate and (d) butyl orotate at 2 °C / min in PHBH is shown.

[0009] Figures 3A-3D The nucleation efficiencies of (a) methyl orotic acid, (b) ethyl orotic acid, (c) propyl orotic acid and (d) butyl orotic acid in PHBH under different loadings are shown.

[0010] Figures 4A-4D POM images of (a) methyl orotic acid, (b) ethyl orotic acid, (c) propyl orotic acid and (d) butyl orotic acid at different concentrations in PHBH at 50 °C are shown.

[0011] Figures 5A-5D SEM images of orotic acid derivatives at different concentrations in PHBH are shown: (a) methyl orotic acid, (b) ethyl orotic acid, (c) propyl orotic acid, and (d) butyl orotic acid.

[0012] Figures 6A-6D The molecular orientation of (a) methyl orotic acid, (b) ethyl orotic acid, (c) propyl orotic acid and (d) butyl orotic acid within their crystal cells is shown.

[0013] The accompanying drawings illustrate only exemplary embodiments and should therefore not be considered as limiting the scope of the description herein, as other equivalent embodiments are also within the scope and spirit of this disclosure. Elements and features shown in the drawings are not necessarily drawn to scale; rather, the emphasis is on clearly illustrating the principles of the embodiments. Additionally, certain dimensions may be enlarged to help visually convey certain principles. In the drawings, similar reference numerals between figures refer to similar or corresponding, but not necessarily identical, elements. Detailed Implementation

[0014] Those skilled in the art to which the disclosed compositions and methods belong will appreciate the teachings presented in the foregoing description and associated drawings. Many modifications and other embodiments of the disclosed contents will therefore occur to them. It should be understood that this disclosure is not intended to be limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Those skilled in the art will recognize many variations and modifications to the aspects described herein. These variations and modifications are intended to be included in the teachings of this disclosure and are covered by the claims herein.

[0015] Although specific terms are used in this document, they are used only in a general and descriptive sense and are not intended for restrictive purposes.

[0016] As will be apparent to those skilled in the art, each of the individual embodiments described and shown herein has discrete components and features that can be readily separated from or combined with features of any of the other embodiments without departing from the scope or spirit of this disclosure.

[0017] Any method described may be performed in the order of the described events or in any other logically possible order. That is, unless expressly stated otherwise, it is never intended to interpret any method or aspect set forth herein as requiring its steps to be performed in a particular order. Therefore, where a method claim does not specifically state in the claims or specification that the steps are limited to a particular order, no inference of order is ever made in any respect. This applies to any possible non-expressive basis for interpretation, including matters of logic concerning the arrangement of steps or the flow of operations, the general meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0018] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with the cited publications. The publications discussed herein are provided only for informational purposes prior to the filing date of this application. Nothing herein should be construed as an admission that the invention is not entitled to any prior art prior to such publications. Furthermore, the publication date provided herein may differ from the actual publication date, which may require independent verification.

[0019] Although aspects of this disclosure may be described and claimed in specific statutory categories, such as the systems statutory category, this is only for convenience, and those skilled in the art will understand that each aspect of this disclosure may be described and claimed in any statutory category.

[0020] It should also be understood that the terminology used herein is for descriptive purposes only and is not intended to be restrictive. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods pertain. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having the same meaning as they have in the context of this specification and the relevant field, and should not be construed as having an idealized or overformal meaning unless expressly defined herein.

[0021] Before describing various aspects of this disclosure, the following definitions are provided and should be used unless otherwise indicated. Other terms may be defined elsewhere in this disclosure. definition

[0022] As used herein, “comprising” should be interpreted as specifying the presence of the referred feature, integer, step, or component, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Furthermore, each of the terms “by,” “comprising,” “comprises,” “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” “having,” and “such as” is used in its open, non-restrictive sense and may be used interchangeably. Further, the term “comprising” is intended to include instances and aspects covered by the terms “substantially constitutes” and “consistent with.” Similarly, the term “substantially constitutes” is intended to include instances covered by the term “consistent with.”

[0023] As used in the specification and appended claims, the singular forms “a,” “an,” and “the” include plural indicators unless the context clearly specifies otherwise. Thus, for example, references to “solvent” include, but are not limited to, mixtures or combinations of two or more such solvents.

[0024] It should be understood that ratios, concentrations, amounts, and other numerical data may be expressed in range format herein. It will be further understood that each endpoint of a range is significant both relative to and independent of the other endpoint. It should also be understood that numerous values ​​are disclosed herein, and each value is also disclosed herein as “about” a specific value other than the value itself. For example, if the value is disclosed as “10,” then “about 10” is also disclosed. In this document, a range may be expressed as from “about” one specific value and / or to “about” another specific value. Similarly, when a value is expressed as an approximation using the antecedent “about,” it should be understood that the specific value forms another aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0025] When referring to a range, another aspect includes from one specific value and / or to another specific value. For example, when the range includes one or two limits, the range excluding any one or two of the included limits is also included within this disclosure; for example, the phrase "x to y" includes a range from 'x' to 'y', as well as ranges greater than 'x' and less than 'y'. A range can also be expressed as an upper limit, such as 'about x, y, z or less', and should be interpreted as including a specific range of 'about x', 'about y', and 'about z', as well as a range of 'less than x', 'less than y', and 'less than z'. Similarly, the phrase 'about x, y, z or greater' should be interpreted as including a specific range of 'about x', 'about y', and 'about z', as well as a range of 'greater than x', 'greater than y', and 'greater than z'. Additionally, the phrase "about 'x' to 'y'" includes "about 'x' to about 'y'", where 'x' and 'y' are numerical values.

[0026] It should be understood that this range format is used for convenience and brevity, and therefore should be interpreted flexibly to include not only the numerical values ​​explicitly stated as the limits of the range, but also all individual numerical values ​​or subranges covering the range, as if each numerical value and subrange were explicitly stated. For example, the numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly stated value of about 0.1% to about 5%, but also the individual values ​​(e.g., about 1%, about 2%, about 3%, and about 4%) and subranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2% and about 0.5% to about 4.4%, and other possible subranges) within the indicated range.

[0027] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the quantity or value in question can be an exact value or a value that provides an equivalent result or effect to that stated in the claims or taught herein. That is, it should be understood that quantities, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller as needed to reflect tolerances, conversion factors, rounding, measurement errors, and other factors known to those skilled in the art to obtain an equivalent result or effect. In some cases, it is not reasonable to determine a value that provides an equivalent result or effect. In such cases, it should generally be understood that, as used herein, unless otherwise indicated or inferred, “about” and “at or about” indicate a value indicating a variation of ±10%. Generally, quantities, sizes, formulations, parameters, or other quantities or characteristics are “about,” “approximate,” or “at or about,” whether explicitly stated or not. It should be understood that when “about,” “approximately,” or “equal to or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless otherwise specifically stated.

[0028] Unless otherwise expressly stated, it is not intended to interpret any method set forth herein as requiring its steps to be performed in a particular order. Therefore, no inference of order is intended in any respect unless the method claims do not actually describe the order in which the steps are followed, or unless the claims or description specifically state that the steps are limited to a particular order. This applies to any possible non-expressive basis for interpretation, including: logical questions relating to the arrangement of steps or the flow of operations; simple meanings derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0029] The components used to prepare the compositions disclosed herein, as well as the compositions themselves used in the methods disclosed herein, are disclosed herein. These and other materials are disclosed herein, and it should be understood that while specific references to every individual and collective combination and arrangement of these materials cannot be explicitly disclosed, each is specifically considered and described herein. For example, if a particular compound is disclosed and discussed, and various modifications that may be made to multiple molecules comprising the compound are discussed, then each combination and arrangement and possible modifications in the compound are specifically contemplated unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C and a class of molecules D, E, and F are disclosed, and an example of the combination molecule AD is disclosed, then each combination is contemplated individually and collectively, even if each combination is not described separately; this means that combinations AE, AF, BD, BE, BF, CD, CE, and CF are considered disclosed. Similarly, any subsets or combinations of these are also disclosed. Thus, for example, subgroups AE, BF, and CE would be considered disclosed. This concept applies to all aspects of this application, including but not limited to the steps in methods for preparing and using the compositions of the invention. Therefore, if various additional steps are available, it should be understood that each of these additional steps can be performed using any particular embodiment or combination of embodiments of the method of the present invention.

[0030] It should be understood that the compositions disclosed herein have certain functions. This document discloses certain structural requirements for performing the disclosed functions, and it should be understood that multiple structures exist that can perform the same function associated with the disclosed structures, and these structures will generally achieve the same result.

[0031] As used herein, the terms “optional” or “optionally” mean that an event or situation described below may or may not occur, and the description includes both cases in which the event or situation occurs and cases in which the event or situation does not occur.

[0032] As used herein, the term "ester" is derived from the formula -C(O)OA. 1 It means that A 1 It can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, cycloynyl, aryl or heteroaryl as described herein.

[0033] As used herein, the term "amide" is derived from the formula -C(O)NHA. 1 It means that A 1 It can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, cycloynyl, aryl or heteroaryl as described herein.

[0034] As used herein, the term "alkyl" is a branched or unbranched saturated hydrocarbon group having 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, etc. Alkyl groups can be cyclic or acyclic. Alkyl groups can be branched or unbranched. Alkyl groups can also be substituted or unsubstituted. For example, an alkyl group can be substituted with one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxyl, nitro, silyl, sulfonyl-oxy, or thiol, as described herein. "Lower alkyl" is an alkyl group containing one to six (e.g., one to four) carbon atoms. The term alkyl can also be C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, etc., up to and including C1-C24 alkyl.

[0035] Throughout this specification, "alkyl" is generally used to refer to both unsubstituted and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying one or more specific substituents on the alkyl group. For example, the terms "halogenated alkyl" or "haloalkyl" specifically refer to an alkyl group substituted with one or more halides, such as fluorine, chlorine, bromine, or iodine. Alternatively, the term "monohalogenated alkyl" specifically refers to an alkyl group substituted with a single halide, such as fluorine, chlorine, bromine, or iodine. The term "polyhalogenated alkyl" specifically refers to an alkyl group independently substituted with two or more halides, i.e., each halide substituent need not be identical to another halide substituent, and multiple instances of halide substituents need not be on the same carbon. The term "alkoxyalkyl" specifically refers to an alkyl group substituted with one or more alkoxy groups, as described below. The term "aminoalkyl" specifically refers to an alkyl group substituted with one or more amino groups. The term "hydroxyalkyl" specifically refers to an alkyl group substituted with one or more hydroxyl groups. When “alkyl” is used in one context and a specific term such as “hydroxyalkyl” is used in another context, it does not imply that the term “alkyl” also refers to a specific term such as “hydroxyalkyl”.

[0036] As used herein, the term "cycloalkyl" refers to a non-aromatic carbon-based ring consisting of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, etc. The term "heterocycloalkyl" is a type of cycloalkyl group as defined above and is included within the meaning of the term "cycloalkyl" in which at least one carbon atom of the ring is replaced by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocycloalkyl groups can be substituted or unsubstituted. Cycloalkyl and heterocycloalkyl groups can be substituted with one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxyl, nitro, silyl, sulfo-oxo, or thiol groups as described herein.

[0037] As used herein, the term "aryl" is a group containing any carbonyl aromatic group, including but not limited to benzene, naphthalene, phenyl, biphenyl, anthracene, etc. Aryl groups can be substituted or unsubstituted. An aryl group can be substituted by one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, -NH2, carboxylic acid, ester, ether, halide, hydroxyl, ketone, azide, nitro, silyl, sulfonyl-oxy, or thiol as described herein. The term "biaryl" is a specific type of aryl group and is included in the definition of "aryl". Additionally, an aryl group can be a monocyclic structure or contain a polycyclic structure, which can be a fused ring structure or linked by one or more bridging groups, such as carbon-carbon bonds. For example, a biaryl group is two aryl groups linked together by a fused ring structure, as in naphthalene, or linked by one or more carbon-carbon bonds, as in biphenyl. Fused and aryl groups, including but not limited to indene and naphthalene groups, are also contemplated.

[0038] As used herein, the term "heteroaryl" refers to an aromatic group having at least one heteroatom incorporated into a ring of aromatic groups. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, wherein N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. Heteroaryl groups can be substituted or unsubstituted. Heteroaryl groups can be substituted by one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxyl, nitro, silyl, sulfo-oxo, or thiol groups as described herein. Heteroaryl groups can be monocyclic or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furanyl, imidazolyl, pyrimidinyl, tetrazolyl, thiophene, pyridinyl, pyrroleyl, N-methylpyrroleyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophene, indolyl, inzolyl, benzoimidazolyl, imidazopyridyl, pyrazolopyridyl, and pyrazolopyrimidinyl. Other non-limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, thiophene, pyrazolyl, imidazolyl, benzo[…]. d Oxazolyl, benzo[ d Thiazolyl, quinolinyl, quinazolinyl, indazole, imidazo[1,2-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl and pyrido[2,3-b]pyrazinyl.

[0039] As used herein, the term "alkenyl" is a hydrocarbon group having 2 to 24 carbon atoms in a structural formula containing at least one carbon-carbon double bond. For example, (A...) 1 A 2 C=C(A) 3 A 4 Asymmetric structures, such as those for..., are intended to include... E and Z Both isomers. This can be assumed in the structural formula herein of which an asymmetric alkene is present, or it can be explicitly represented by the bond symbol C=C. The alkenyl group can be substituted with one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxyl, ketone, azide, nitro, silyl, sulfonyl-oxo, or thiol as described herein.

[0040] As used herein, the term "cycloalkenyl" is a non-aromatic carbon-based ring consisting of at least three carbon atoms and containing at least one carbon-carbon double bond, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornyl, etc. The term "heterocyclic alkenyl" is a type of cycloalkenyl group as defined above and is included within the meaning of the term "cycloalkenyl" in which at least one carbon atom of the ring is replaced by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. Cycloalkenyl and heterocyclic alkenyl groups can be substituted or unsubstituted. Cycloalkenyl and heterocyclic alkenyl groups may be substituted with one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxyl, ketone, azide, nitro, silyl, sulfonyl-oxo, or thiol as described herein.

[0041] As used herein, the term "alkynyl" is a hydrocarbon group having 2 to 24 carbon atoms in a structural formula containing at least one carbon-carbon triple bond. The alkynyl group may be unsubstituted or may be substituted by one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxyl, ketone, azide, nitro, silyl, sulfonyl-oxy, or thiol as described herein. Orylate esters and amides and their preparation and use methods

[0042] This article describes orotic esters and amides as nucleating agents for crystallizing molten poly(hydroxyalkanoates). The orotic esters and amides are soluble in the molten poly(hydroxyalkanoates) and exhibit high nucleation efficiency. Using the orotic esters and amides described herein provides several advantages for producing articles composed of the poly(hydroxyalkanoates).

[0043] Melt-soluble nucleating agents that dissolve into the molten polymer melt at high temperatures and then recrystallize upon cooling to form nucleating crystals are of particular interest; however, they are very rare. Melt-soluble nucleating agents are desirable because they 1) provide a homogeneous melt that is more conducive to the production of small extrusions (i.e., films, fibers, etc.), and 2) because they ensure their own uniform distribution during shear processing, and thus produce a more consistent product. The orot esters and amides described herein meet this requirement.

[0044] On the one hand, the orotic esters and amides described herein are completely soluble in molten poly(hydroxyalkanoates). On the other hand, when the orotic esters and amides reach 10% by weight of the molten composition, the orotic esters and amides described herein are completely soluble in molten poly(hydroxyalkanoates). The solubility of the orotic esters and amides described herein can be determined using techniques known in the art. Furthermore, the molten composition consisting of poly(hydroxyalkanoates) and orotic esters or amides can be visually inspected to determine the presence of any solid particles of orotic esters or amides.

[0045] On the one hand, the ester of the orotic acid is of formula I. Where R 1 It is a branched or straight-chain C1 to C10 alkyl, C3 to C7 cycloalkyl or aryl.

[0046] On the one hand, R in Equation I 1 It is methyl, ethyl, propyl, or butyl. On the one hand, esters of orotic acid having formula I are orotic acid and alcohol R. 1 The reaction products between OH groups, where R 1 As defined above (e.g., methanol, ethanol, propanol, butanol, etc.). Examples provide non-limiting steps for the preparation and purification of orotic acid esters as described herein.

[0047] On the other hand, the amide of orotic acid is of formula II. Where R 2 It is hydrogen, branched or straight-chain C1 to C10 alkyl, C3 to C7 cycloalkyl or aryl.

[0048] On the one hand, R in Equation II 2 It is hydrogen. On the other hand, R in formula II 2 It is cyclohexyl. On the other hand, R in formula II 2 It is a substituted or unsubstituted phenyl group. On the one hand, the ester of orotic acid having formula II is orotic acid reacted with amine R. 2 The reaction products between NH2, where R 2 As defined above. Examples provide non-limiting steps for the preparation and purification of orotic amides as described herein.

[0049] Polymer crystallization is the process by which a hot, molten (melted) polymer transforms into a solid material upon cooling. The esters and amides of orotic acid described herein are soluble in molten poly(hydroxyalkanoates) at high temperatures but recrystallize in the polymer melt at lower temperatures to form surfaces on which polymer crystals readily grow.

[0050] On one hand, the method for crystallizing poly(hydroxyalkanoates) includes (a) The poly(hydroxyalkanoate) and a first nucleating agent are mixed, wherein the first nucleating agent comprises an ester of orotic acid, an amide of orotic acid, or a combination thereof, to produce a first composition; (b) Heating the first mixture to a temperature above the melting point of the poly(hydroxyalkanoate) for a time sufficient to melt the poly(hydroxyalkanoate) to produce a molten composition; and (c) Cool the molten composition to produce crystalline poly(hydroxyalkanoate).

[0051] Step (a) involves mixing the poly(hydroxyalkanoate) and the first nucleating agent such that the first nucleating agent is uniformly dispersed (i.e., homogeneous) throughout the poly(hydroxyalkanoate). The mixing of the poly(hydroxyalkanoate) and the first nucleating agent can be performed using techniques known in the art.

[0052] In some aspects, the first nucleating agent may comprise two or more different compounds having structures in Formulas I and II above. On one hand, the first nucleating agent comprises a first ester or amide of orotic acid having a first chemical structure and a second ester or amide of orotic acid having a second chemical structure, wherein the first chemical structure is different from the second chemical structure. On another hand, the nucleating agent may comprise two different orotic esters having Formula I. On the other hand, the nucleating agent may comprise two different orotic amides having Formula II. On yet another hand, the nucleating agent may comprise a combination of orotic esters and amides having Formulas I and II, respectively.

[0053] In some respects, additional components may be added to the poly(hydroxyalkanoate) and the first nucleating agent. On one hand, a solid filler or a second nucleating agent may be added to the poly(hydroxyalkanoate) and the first nucleating agent, wherein the solid filler or the second nucleating agent cannot be melt-dissolved in the molten composition. On one hand, the second melt-insoluble nucleating agent may be orotic acid. On the other hand, no filler or other melt-insoluble material may be combined with the poly(hydroxyalkanoate) and the first nucleating agent.

[0054] The amount of the first nucleating agent combined with the poly(hydroxyalkanoate) can vary. On one hand, the first nucleating agent accounts for about 0.01% to about 10.0% by weight of the polymer composition consisting of the poly(hydroxyalkanoate) and the first nucleating agent. On the other hand, the first nucleating agent is about 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, or 10.0% by weight, wherein any value can be the lower or upper limit of a range (e.g., 0.2% to 1.5% by weight).

[0055] On the one hand, when the first nucleating agent is methyl orotate, ethyl orotate, propyl orotate, the first nucleating agent accounts for about 0.01% by weight to about 1.0% by weight or 0.01% by weight, 0.05% by weight, 0.1% by weight, 0.2% by weight, 0.3% by weight, 0.4% by weight, 0.5% by weight, 0.6% by weight, 0.7% by weight, 0.8% by weight, 0.9% by weight, or 1.0% by weight, wherein any value may be the lower end and upper end of a range (e.g., 0.2% by weight to 0.8% by weight).

[0056] On the one hand, when the first nucleating agent is methyl orotate (R 1 When the first nucleating agent is methyl in Formula I, it accounts for about 0.8% to about 1.2% by weight or 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.05%, 1.10%, 1.15%, or 1.2% by weight of the polymer composition, wherein any value may be the lower and upper limits of a range (e.g., 0.85% to 1.15% by weight).

[0057] On the one hand, when the first nucleating agent is ethyl orotate (R 1 When the first nucleating agent is an ethyl group in Formula I, the first nucleating agent accounts for about 0.1% to about 0.3% by weight or 0.1%, 0.15%, 0.2%, 0.25% by weight or 0.3% by weight of the polymer composition, wherein any value may be the lower end and upper end of a range (e.g., 0.85% by weight to 1.15% by weight).

[0058] On the one hand, when the first nucleating agent is propyl orotate (R 1When the first nucleating agent is propyl in Formula I, it comprises about 0.6 wt% to about 1.0 wt% or 0.6 wt%, 0.65 wt%, 0.7 wt%, 0.75 wt%, 0.80 wt%, 0.85 wt%, 0.9 wt%, 0.95 wt% or 1.0 wt% of the polymer composition, wherein any value may be the lower end and upper end of a range (e.g., 0.65 wt% to 0.85 wt%).

[0059] On the one hand, when the first nucleating agent is orotic butyl ester (R 1 When the first nucleating agent is butyl in Formula I, it comprises about 0.4 wt% to about 0.8 wt% or 0.4 wt%, 0.45 wt%, 0.5 wt%, 0.55 wt%, 0.6 wt%, 0.65 wt%, 0.7 wt%, 0.75 wt% or 0.8 wt% of the polymer composition, wherein any value may be the lower end and upper end of a range (e.g., 0.45 wt% to 0.65 wt%).

[0060] The poly(hydroxyalkanoate) can be a homopolymer or a copolymer. In one aspect, the poly(hydroxyalkanoate) is a poly(hydroxyalkanoate) homopolymer selected from the group consisting of: poly(3-hydroxybutyrate), polylactic acid, polyglycolic acid, and poly(4-hydroxybutyrate).

[0061] On one hand, the poly(hydroxyalkanoate) is a copolymer of 3-hydroxybutyrate and at least one comonomer selected from the group consisting of: 3-hydroxypropionate, 3-hydroxyvalerate, 3-hydroxyhexanoate, 3-hydroxyheptanoate, 3-hydroxyoctanoate, 3-hydroxynonanoate, 3-hydroxydecanoate, 3-hydroxydodecanate, 3-hydroxydodecenoate, 3-hydroxytetradecanoate, 3-hydroxytetradecanoate, 3-hydroxyhexadecanoate, 3-hydroxyoctadecanoate, 3-hydroxy-4-pentenoate, 4-hydroxybutyrate, 4-hydroxyvalerate, 5-hydroxyvalerate, and 6-hydroxyhexanoate.

[0062] On one hand, the poly(hydroxyalkanoate) is poly(3-hydroxybutyrate-co-3-hydroxypropionate), poly(3-hydroxybutyrate-co-4-hydroxybutyrate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxybutyrate-co-3-hydroxyhexanoate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate), and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate-co-3-hydroxycaproate-co-3-hydroxyhexanoate) and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate-co-3-hydroxyoctanoate-co-3-hydroxydecanoate-co-3-hydroxydodecanate-co-3-hydroxydodecenoate).

[0063] Depending on the application or the product to be produced, two or more different poly(hydroxyalkanoates) may be combined with the nucleating agents described herein. The molecular weight of the poly(hydroxyalkanoates) can vary. On one hand, the molecular weight of the poly(hydroxyalkanoates) is from about 10,000 to about 3,000,000. On the other hand, the molecular weight of the poly(hydroxyalkanoates) is from about 300,000 to about 1,000,000.

[0064] After mixing the poly(hydroxyalkanoate) and the described nucleating agent, the resulting polymer composition is heated to a temperature above the melting point of the poly(hydroxyalkanoate) for a time sufficient to melt the poly(hydroxyalkanoate) to produce a molten polymer composition.

[0065] The temperature and time required to completely melt the poly(hydroxyalkanoate) to produce a molten polymer composition consisting of a nucleating agent can vary depending on the choice of poly(hydroxyalkanoate) and the method used to heat it. During the heating process, the nucleating agent described herein dissolves in the molten poly(hydroxyalkanoate). Alternatively, at a temperature below the melting temperature of the nucleating agent, the poly(hydroxyalkanoate) can be melted with the nucleating agent described herein to produce a single-phase solution of both the poly(hydroxyalkanoate) and the nucleating agent.

[0066] Compared to other nucleating agents known in the art, the nucleating agents described herein require lower melting temperatures. For example, pentaerythritol requires a temperature of approximately 180°C to dissolve in poly(hydroxyalkanoates). On the other hand, the poly(hydroxyalkanoates) and nucleating agents described herein are heated to temperatures below 175°C.

[0067] On the one hand, the poly(hydroxyalkanoate) described herein is heated with a nucleating agent to about 30°C to about 80°C, above the melting point of the poly(hydroxyalkanoate), or to 30°C, 40°C, 50°C, 60°C, 70°C, or 80°C, above the melting point of the poly(hydroxyalkanoate), wherein any value may be the lower or upper limit of the range (40°C to 70°C). On the other hand, the poly(hydroxyalkanoate) described herein is heated with a nucleating agent from about 0°C to about 225°C, preferably from about 100°C to about 225°C, or preferably from 150°C to about 225°C, for about 2 minutes to about 1 hour, preferably from 2 minutes to 30 minutes, or preferably from 2 minutes to 10 minutes.

[0068] On the one hand, the molten polymer composition of poly(hydroxyalkanoates) and nucleating agents described herein can be produced by an extruder. The extruder may have an electric motor to rotate the screw inside the extruder. The extruder can be a single-screw or twin-screw extruder made of individual elements of various sizes and pitches suitable for mixing or kneading the specific material used. In some instances, the extruder has a twin-screw design. Extruders can produce many different articles, including but not limited to sheets, films, or fibers.

[0069] The poly(hydroxyalkanoate) described herein, along with a nucleating agent and optional components (e.g., fillers), is added to an extruder through one or more ports. The various components can be added as a melt or as appropriately sized solid particles, such as fragments or granules, which melt in sections as they are mixed in the barrel of the extruder. The contents of the extruder can be heated to melt the composition.

[0070] In some respects, foaming agents can be added to produce poly(hydroxyalkanoate) foams. Supercritical fluids can be added to the melt as physical foaming agents. In a particular instance, poly(hydroxyalkanoate) foams are prepared using physical foaming agents that cause the composition to foam after it leaves the extruder, and thus the poly(hydroxyalkanoate) foam is substantially free of chemical foaming agents or their decomposition products.

[0071] On the other hand, if a chemical foaming agent is used, the processing (melting) temperature can be sufficiently lower than the temperature at which the foaming agent will be triggered. To foam the composition, the temperature near the extruder exit can be raised to near or equal to the triggering temperature of the chemical foaming agent, thereby producing a chemically foamed poly(hydroxyalkanoate) foam when the composition leaves the extruder (e.g., when the composition is injected into an injection mold).

[0072] Alternatively or additionally, physical foaming agents can be used to foam the composition to form physically foamed poly(hydroxyalkanoate) foams, or physically and chemically foamed poly(hydroxyalkanoate) foams. For example, supercritical fluids such as supercritical carbon dioxide or supercritical nitrogen can be mixed with molten polymer composition in the barrel of an extruder to form a single-phase solution. As the single-phase solution exits the extruder, the pressure drop between the higher pressure inside the extruder and the lower pressure outside the extruder causes the supercritical fluid to transition to a gaseous phase and foams the molten polymer composition.

[0073] On the other hand, molded articles composed of poly(hydroxyalkanoates) and nucleating agents can be produced by injection molding. Injection molding can utilize a screw injector, which allows for the maintenance and control of pressure within the injector barrel, where the molten polymer composition is injected into a mold. In some aspects, a foaming agent, as described above, can be mixed into the molten polymer composition within the injection barrel and then injected into the mold. For example, the injection molding machine can allow supercritical fluids, such as carbon dioxide or nitrogen, to be metered and delivered to the composition prior to injection. The supercritical fluid can then expand to generate cell nuclei to form physical foam within the mold.

[0074] Once an article comprising a molten polymer composition consisting of poly(hydroxyalkanoate) and a nucleating agent is produced, the article is cooled to initiate crystallization of the molten poly(hydroxyalkanoate) and solidify the polymer in the article. On one hand, the molten composition is cooled to approximately 60°C to approximately 110°C for approximately 1 minute to approximately 1 hour to allow the poly(hydroxyalkanoate) to crystallize.

[0075] The nucleating agents described herein exhibit high nucleation efficiency. Without being bound by theory, the improved nucleation efficiency is attributed to the melt solubility of the described nucleating agents in molten poly(hydroxyalkanoates). Specifically, the nucleation efficiency of the described nucleating agents is approximately 60% to approximately 80%. Methods for calculating the nucleation efficiency are provided in the examples. Therefore, using the nucleating agents described herein provides an efficient and cost-effective method for producing poly(hydroxyalkanoate) articles. aspect

[0076] Aspect 1. A polymer composition comprising a poly(hydroxyalkanoate) and a nucleating agent, wherein the nucleating agent comprises an ester of orotic acid, an amide of orotic acid, or a combination thereof.

[0077] Aspect 2. The composition according to aspect 1, wherein the ester of the orotic acid is of formula I. Where R 1 It is a branched or straight-chain C1 to C10 alkyl, C3 to C7 cycloalkyl or aryl.

[0078] Aspect 3. The composition according to aspect 2, wherein R 1 The acid is methyl, ethyl, propyl, or butyl.

[0079] Aspect 4. The composition according to aspect 1, wherein the orotic acid amide is of formula II. Where R 2It is hydrogen, branched or straight-chain C1 to C10 alkyl, C3 to C7 cycloalkyl or aryl.

[0080] Aspect 5. The composition according to aspect 4, wherein R 2 It is hydrogen.

[0081] Aspect 6. The composition according to aspect 4, wherein R 2 It is cyclohexyl.

[0082] Aspect 7. The composition according to aspect 4, wherein R 2 It is either a substituted or unsubstituted phenyl group.

[0083] Aspect 8. The composition according to any one of Aspects 1 to 7, wherein the nucleating agent accounts for about 0.01% to about 10.0% by weight of the polymer composition.

[0084] Aspect 9. The composition according to aspect 1, wherein the nucleating agent is methyl orotic acid, ethyl orotic acid, propyl orotic acid, or butyl orotic acid, and the nucleating agent accounts for about 0.01% by weight to about 1.0% by weight of the polymer composition.

[0085] Aspect 10. The composition according to aspect 1, wherein the nucleating agent is methyl orotate, and the nucleating agent accounts for about 0.8% to about 1.2% by weight of the polymer composition.

[0086] Aspect 11. The composition according to aspect 1, wherein the nucleating agent is ethyl orotate, and the nucleating agent accounts for about 0.1% to about 0.3% by weight of the polymer composition.

[0087] Aspect 12. The composition according to aspect 1, wherein the nucleating agent is propyl orotate, and the nucleating agent accounts for about 0.6% to about 1.0% by weight of the polymer composition.

[0088] Aspect 13. The composition according to aspect 1, wherein the nucleating agent is butyl orotate, and the nucleating agent accounts for about 0.4% to about 0.8% by weight of the polymer composition.

[0089] Aspect 14. The composition according to any one of Aspects 1 to 13, wherein the nucleating agent is moltenly dissolved in the poly(hydroxyalkanoate).

[0090] Aspect 15. The composition according to any one of Aspects 1 to 14, wherein the poly(hydroxyalkanoate) is a copolymer of 3-hydroxybutyrate and at least one comonomer selected from the group consisting of: 3-hydroxypropionate, 3-hydroxyvalerate, 3-hydroxyhexanoate, 3-hydroxyheptanoate, 3-hydroxyoctanoate, 3-hydroxynonanoate, 3-hydroxydecanoate, 3-hydroxydodecanate, 3-hydroxydodecenoate, 3-hydroxytetradecanoate, 3-hydroxytetradecanoate, 3-hydroxyhexadecanoate, 3-hydroxyoctadecanoate, 3-hydroxy-4-pentenoate, 4-hydroxybutyrate, 4-hydroxyvalerate, 5-hydroxyvalerate, and 6-hydroxyhexanoate.

[0091] Aspect 16. The composition according to any one of Aspects 1 to 14, wherein the poly(hydroxyalkanoate) is selected from the group consisting of: poly(3-hydroxybutyrate-co-3-hydroxypropionate), poly(3-hydroxybutyrate-co-4-hydroxybutyrate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxybutyrate-co-3-hydroxyhexanoate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate), and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate-co-3-hydroxycaproate-co-3-hydroxyhexanoate).

[0092] Aspect 17. The composition according to any one of Aspects 1 to 14, wherein the poly(hydroxyalkanoate) is a polyhydroxyalkanoate homopolymer selected from the group consisting of: poly(3-hydroxybutyrate), polylactic acid, polyglycolic acid and poly(4-hydroxybutyrate).

[0093] Aspect 18. The composition according to any one of Aspects 1 to 14, wherein the polyhydroxyalkanoate poly(hydroxybutyrate-co-hydroxyhexanoate).

[0094] Aspect 19. A method for crystallizing poly(hydroxyalkanoates), the method comprising... (a) The poly(hydroxyalkanoate) and a first nucleating agent are mixed, wherein the first nucleating agent comprises an ester of orotic acid, an amide of orotic acid, or a combination thereof, to produce a first composition; (b) Heating the first mixture to a temperature above the melting point of the poly(hydroxyalkanoate) for a time sufficient to melt the poly(hydroxyalkanoate) to produce a molten composition; and (c) Cool the molten composition to produce crystalline poly(hydroxyalkanoate).

[0095] Aspect 20. The method according to aspect 19, wherein during step (b), at least a portion of the first nucleating agent dissolves in the molten composition.

[0096] Aspect 21. The method according to aspect 19, wherein during step (b), a single-phase solution of the poly(hydroxyalkanoate) and the first nucleating agent is formed, wherein the first nucleating agent is dissolved in the molten poly(hydroxyalkanoate).

[0097] Aspect 22. The method according to any one of Aspects 19 to 21, wherein the first nucleating agent has a first melting temperature, wherein in step (b), the poly(hydroxyalkanoate) is melted at a temperature below the first melting temperature to form a single-phase solution of the poly(hydroxyalkanoate) and the first nucleating agent.

[0098] Aspect 23. The method according to any one of Aspects 19 to 22, wherein step (b) comprises heating the poly(hydroxyalkanoate) and the first nucleating agent to a temperature below 175°C.

[0099] Aspect 24. The method according to any one of Aspects 19 to 22, wherein the first nucleating agent comprises a first ester or amide of orotic acid having a first chemical structure and a second ester or amide of orotic acid having a second chemical structure, wherein the first chemical structure is different from the second chemical structure.

[0100] Aspect 25. The method according to any one of Aspects 19 to 24, wherein the first composition further comprises a solid filler or a second nucleating agent, wherein the solid filler or the second nucleating agent is not fusibly soluble in the molten composition.

[0101] Aspect 26. The method according to any one of Aspects 19 to 24, wherein the first composition does not include a solid filler or a second nucleating agent, wherein the solid filler or the second nucleating agent is not molten and soluble in the molten composition.

[0102] Aspect 27. The method according to aspect 26, wherein the second nucleating agent is orotic acid.

[0103] Aspect 28. The method according to any one of Aspects 19 to 26, wherein in step (b), the first composition is heated from about 30°C to about 80°C, above the melting point of the poly(hydroxyalkanoate).

[0104] Aspect 29. The method according to any one of aspects 19 to 26, wherein in step (b), the first composition is heated from about 0°C to about 225°C for about 2 minutes to about 1 hour.

[0105] Aspect 30. The method according to any one of aspects 19 to 28, wherein in step (c), the molten composition is cooled to about 60°C to about 110°C for about 1 minute to about 1 hour.

[0106] Aspect 31. The method according to any one of aspects 19 to 30, wherein the first composition is extruded during step (b).

[0107] Aspect 32. The method according to aspect 31, wherein the first composition is extruded into a sheet, film or fiber.

[0108] Aspect 33. The method according to any one of aspects 19 to 30, wherein during step (b), the first composition is injected into a mold.

[0109] Aspect 34. The method according to aspect 33, wherein after the first composition is injected into the mold to form the molten composition, the molten composition is foamed.

[0110] Aspect 35. The method according to aspect 34, wherein the first composition further comprises a foaming agent.

[0111] Aspect 36. The method according to aspect 35, wherein the foaming agent comprises a supercritical fluid foaming agent.

[0112] Aspect 37. A crystalline poly(hydroxyalkanoate) produced by the method according to any one of aspects 19 to 36.

[0113] Aspect 38. A method for extruding poly(hydroxyalkanoates), the method comprising: (a) Forming a first composition comprising molten poly(hydroxyalkanoate) and a first nucleating agent, wherein the first nucleating agent comprises an ester or orotic acid, an amide of orotic acid, or a combination thereof; (b) Extruding the first composition to produce an extruded composition; and (c) Lowering the temperature of the extruded composition to initiate crystallization of the molten poly(hydroxyalkanoate) and to solidify the extruded composition.

[0114] Aspect 39. A method for injection molding poly(hydroxyalkanoate), the method comprising: (a) Forming a first composition comprising molten poly(hydroxyalkanoate) and a first nucleating agent, wherein the first nucleating agent comprises an ester of orotic acid, an amide of orotic acid, or a combination thereof; (b) Injecting the first composition into a mold to produce an injected molten composition; (c) Reducing the temperature of the injected molten composition in the mold, reducing the pressure in the mold, or a combination thereof, to initiate crystallization of the poly(hydroxyalkanoate) in the injected molten composition and to solidify the injected molten composition in the mold; and (d) Remove the cured composition from the mold.

[0115] Aspect 40. The method according to any one of aspects 19 to 39, wherein the nucleation efficiency of the method is about 60% to about 80%.

[0116] Aspect 41. An article of manufacture made by means of the method according to aspect 38 or 39.

[0117] Aspect 42. A compound of formula I Where R 1 It is a branched or straight-chain C1 to C10 alkyl, C3 to C7 cycloalkyl or aryl.

[0118] Aspect 43. A compound of formula II Where R 2 It is hydrogen, branched or straight-chain C1 to C10 alkyl, C3 to C7 cycloalkyl or aryl.

[0119] Aspect 44. A molten polymer composition comprising a molten poly(hydroxyalkanoate) and a nucleating agent, wherein the nucleating agent comprises an ester of orotic acid, an amide of orotic acid, or a combination thereof, wherein at least a portion of the nucleating agent is dissolved in the molten poly(hydroxyalkanoate).

[0120] Aspect 45. The molten polymer composition according to aspect 44, wherein the molten composition comprises a single-phase solution of the molten poly(hydroxyalkanoate) and the nucleating agent, wherein the nucleating agent is dissolved in the molten poly(hydroxyalkanoate).

[0121] Aspect 46. The molten polymer composition according to aspect 44 or 45, wherein the nucleating agent is completely dissolved in the molten poly(hydroxyalkanoate). Example

[0122] Embodiments of this disclosure have now been described; generally, examples illustrate other embodiments. While embodiments of this disclosure have been described in conjunction with examples and corresponding text and drawings, it is not intended to limit the embodiments of this disclosure to these descriptions. Rather, it is intended to cover all alternatives, modifications, and equivalents included within the spirit and scope of the embodiments of this disclosure. Materials and Methods

[0123] Material

[0124] The PHBHHx copolymer was produced at the New Materials Institute (Athens, Georgia, 7.0 mol% hydroxyhexanoic acid, Mw = 628 kDa) and dried in a vacuum oven at 80 °C for at least 72 hours prior to use. Orotic acid monohydrate was purchased from Sigma-Aldrich and dried at 125 °C for at least 24 hours prior to use to remove associated water. Methanol, ethanol, propanol, butanol, sulfuric acid, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), dimethylformamide (DMF), and iodoethane were all purchased from Sigma-Aldrich and used upon supply. Methyl oroticate, propyl oroticate, and butyl oroticate were synthesized by Fischer esterification in very good to excellent yields (87-96%), while ethyl oroticate was shown to be non-reactive. Conversely, ethyl oroticate was obtained in very good yields (85%) via a previously published alternative route. 31

[0125] General Synthesis of Orotic Acids via Fischer Esterification

[0126] Add 12.5 g of anhydrous orotic acid to a 2 L single-necked flask, followed by 1 kg of the corresponding alcohol. Add 12.5 mL of concentrated sulfuric acid. Heat the heterogeneous mixture under reflux until all solids dissolve. Reduce the solvent to approximately 1 / 3 volume by rotary evaporation and cool the liquid to -20 °C. Collect the precipitated solid by filtration and wash it with cooled corresponding alcohol. Maintain the mother liquor at -20 °C for several days and collect a second batch of crystals by filtration, followed by washing with corresponding alcohol. Dry the filtrate under vacuum at 60 °C for 24 hours.

[0127] Synthesis of methyl 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate:

[0128] Follow the standard procedure. After reflux for 5 days, the reaction mixture became homogenized. The combined yield of the first and second batches was 12.0 g (88%). 1 H NMR (600 MHz, CDCl3) δ 11.40 (s, 1H), 11.14 (s, 1H), 6.05 (s,1H), 3.85 (s, 3H).

[0129] Synthesis of propyl 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate:

[0130] Follow the standard procedure. After reflux for 3 days, the reaction mixture became homogenized. The combined yield of the first and second batches was 15.2 g (96%). 1 H NMR (600 MHz, CDCl3) δ 11.40 (s, 1H), 11.15 (s, 1H), 6.05 (s,1H), 4.22 (t, 2H), 1.71 (m, 2H), 0.94 (t, 3H).

[0131] Synthesis of butyl 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate:

[0132] Following standard procedures, the reaction mixture became homogenized after reflux for 18 hours. The combined yield of the first and second batches was 14.8 g (87%). 1 H NMR (600 MHz, CDCl3) δ 11.40 (s, 1H), 11.15 (s, 1H), 6.05 (s,1H), 4.27 (t, 2H), 1.67 (p, 2H), 1.38 (m, 2H), 0.92 (t, 3H).

[0133] Synthesis of ethyl 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate:

[0134] The general procedure for the Fischer esterification of orot esters was applied to the synthesis of ethyl 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylate. However, even after reflux for 7 days, experimental observation (observation of a persistently heterogeneous solution) and by... 1 Incomplete transformation was also observed by 1H NMR monitoring. Instead, the previously published procedure that yielded satisfactory results was followed (Patent WO2007011065A2, 2006). Briefly, 19.1 g of anhydrous orotic acid and 18.6 g of DBU were dissolved in 35 mL of anhydrous DMF. Then 22.9 g (1.2 equivalents) of iodoethane was added, followed by heating to 60 °C for 5 hours. 300 mL of cold water was added to the solution to precipitate white crystals, which were separated by filtration. The mother liquor was allowed to stand at room temperature for 1 day until a second batch of crystals was collected. The combined batch was dried at 60 °C for 24 hours to separate 19.1 g of white powder (85%). 1 H NMR (600MHz, CDCl3) δ 11.40 (s, 1H), 11.14 (s, 1H), 6.05 (s, 1H), 4.31 (q, 2H), 1.30 (t, 3H).

[0135] General Synthesis of Orotic Acid Amides

[0136] Under a nitrogen atmosphere, approximately 18.6 g of orotic acid (anhydrous), 40 mL of thionyl chloride, 1 mL of DMF, and 100 mL of anhydrous toluene were added to a 500 mL round-bottom flask. The heterogeneous mixture was heated under reflux for 3 hours and then cooled to room temperature. The mixture was filtered, and the collected solid was washed three times with anhydrous toluene under nitrogen to give a light brown solid. The light brown solid was dried in a vacuum desiccator and collected in quantitative yield.

[0137] The solid was then suspended in anhydrous DCM or DMF containing 1.0 equivalent of anhydrous pyridine. Then, 1.2–4.0 equivalents of the corresponding amine (cyclohexylamine, ammonium hydroxide, aqueous methylamine, or aniline) were added dropwise to the flask at room temperature. The solution was heated to 40°C overnight. The precipitated solid was collected by filtration and washed three times with water to obtain orotamide.

[0138] melt blending

[0139] Methyl orotic acid, ethyl orotic acid, propyl orotic acid, and butyl orotic acid were manually blended into PHBH powder at concentrations ranging from 0.05 w / w% to 8.0 w / w% to form 7 g samples. The samples were compounded in a Thermo Fisher HAAKE Minilab II conical twin-screw extruder at 150°C and a screw speed of 100 rpm. The samples were allowed to circulate in the extruder for 5 minutes before being extruded into the test line.

[0140] Differential scanning calorimetry (DSC)

[0141] The thermal transitions of the synthesized products and blended samples were measured under nitrogen atmosphere using a TA Discovery 250 differential scanning calorimeter (TA Instruments). Before testing, samples (2–12 mg) were sealed in aluminum disks. The melting point of the synthesized products was determined by measuring the thermal transitions at 10 °C min. -1 The sample is heated to determine the temperature. For compounded samples, a non-isothermal heating program is used, starting at 10°C / min. -1 Begin heating to 200°C to eliminate thermal history, then reduce to 10°C / min. -1 Cool to -20°C. These experiments were also repeated, this time at 2°C min. -1 cool down.

[0142] Polarization optical microscopy (POM)

[0143] Thin extruded sections were added to the stage of an Eclipse LV100N POL polarization microscope (Nikon, MinatoCity, Tokyo, Japan) equipped with LINK software (version 1.2.5.1300, Linkam Scientific Instruments, United Kingdom). The polarizer and analyzer were both set to 0°, and a 1λ (λ = 530 nm) tone plate was added to the optical path. Camera settings (exposure, shutter speed, gain, and white balance) were set to auto-adjustment for optimal image quality. To assess the nucleation efficiency of the synthesized product, the sample was heated to 200°C at a rate of 150°C / min and held for 1 minute, during which time the sample was gently flattened. The sample was then cooled to 50°C at a rate of 30°C / min for nucleation observation.

[0144] Crystal structure determined

[0145] Colorless crystalline samples of each orotic acid derivative were obtained by solvent recrystallization for X-ray crystallography analysis. The methyl derivative was recrystallized from methanol (4 mg / mL), the ethyl from ethanol (14 mg / mL), the propyl from water (4 mg / mL), and the butyl from ethanol (10 mg / mL). The recrystallization solutions were first heated to boiling, filtered through a 0.2 μm PTFE filter, and allowed to stand in sealed vials for 7–9 days. X-ray intensity data were measured at ambient temperature using the ω-scan technique on a Bruker D8 Quest PHOTON 100 CMOS X-ray diffractometer system with an Incoatec Microfocus Source (1µS) monochromatic Mo Ka radiation (l = 0.71073 Å, sealed tube). The data were integrated with the manufacturer's SAINT software, and absorption effects were corrected using the multiple scan method (SADABS). The structure was solved and refined using the BrukerSHELXTL software package (Bruker AXS, Madison WI, USA). 32 The positions of non-hydrogen atoms were determined by successive Fourier map calculations. In the final period of each refinement, all non-hydrogen atoms were refined in anisotropic displacement parameters, while hydrogen atoms were calculated and added to their bonded carbon or nitrogen atoms. The crystal structure arrangement was evaluated using VESTA software. 33

[0146] Scanning electron microscopy (SEM)

[0147] The morphology of large crystals of orotate methyl, ethyl, propyl, and butyl orotate was determined using scanning electron microscopy (FE-SEMl FEI Teneo, ThermoFisher Scientific, USA). Large crystals were placed on aluminum disks covered with double-sided adhesive tape before sputtering at 15–20 nm using a LEIA EM ACE200 high-vacuum sputtering system (Wetzlar, Germany). The crystals were then imaged at an accelerating voltage of 10 kV. The low-temperature fracture surfaces of the mixed samples were similarly observed using a SU9000EA scanning electron microscope (Hitachi, Chiyoda City, Tokyo, Japan). Low-temperature fracture was also performed on POM samples, followed by mounting and sputtering. Results and discussion

[0148] Thermal analysis

[0149] The nucleation properties of the synthesized orotic acid derivatives were first evaluated by differential scanning calorimetry (DSC). Figures 1A-1D Thermochromatograms of orotate derivatives at a standard rate of 10 °C / min are shown. Each derivative was initially evaluated at 1 w / w%, 2 w / w%, 3 w / w%, 4 w / w%, and 5 w / w%. Additional concentrations were added as needed to comprehensively analyze significant variations in the concentration-dependent nucleation behavior of the additives. The presence of exothermic crystallization at different temperatures demonstrates the nucleation of PHBH, with higher temperatures corresponding to better nucleation performance. Crystallization rates can also be defined by relative peak shapes, ranging from broad and flat (indicating slow crystallization) to high and sharp (indicating rapid crystallization). Considering the slow crystallization rate and low temperature of pure PHBH crystallization, rapid crystallization at higher temperatures is considered advantageous in terms of nucleating agent performance. All samples performed relatively well at low concentrations (equal to or below 1.0 w / w%); however, some samples showed significantly reduced performance at higher concentrations. Propyl orotate appears to have the least concentration dependence, exhibiting relatively similar performance over a wider concentration range. In contrast, ethyl orotate exhibited significantly different nucleation properties at concentrations above 1.2 w / w% and below 4.0 w / w%. Butyl orotate appeared to show the same concentration dependence as ethyl orotate, exhibiting no nucleation properties between 1.4 w / w% and 3.0 w / w%. Methyl orotate affected nucleation at all evaluated concentrations above 0.2 w / w%, however, its performance decreased slightly above 1.6 w / w%.

[0150] DSC analysis of all nucleating agents at all concentrations was repeated at a cooling rate of 2°C per minute to establish rate-dependent nucleation performance. The DSC thermograms of the mixtures cooled at 2°C per minute are shown in [image / image / description]. Figures 2A-2D As shown in the figure. Under these conditions, the exothermic crystallization occurred at higher temperatures compared to the sample at 10 °C per minute, because the residence time was longer at higher temperatures, as the cooling process required more time. However, apart from the temperature change, the relative properties of each material remained constant. The most dramatic exothermic crystallization occurred at low concentrations (equal to or below 1.0 w / w%) for each material, while higher concentrations showed a decline in performance. The highest nucleation peak temperatures occurred at 1.0 w / w% (92.42 °C) for methyl orotate, 0.2 w / w% (97.03 °C) for ethyl orotate, 0.8% (93.34 °C) for propyl orotate, and 0.4 w / w% (95.15 °C) for butyl orotate.

[0151] Using Thierry’s previously proposed nucleation efficiency scale percentage, the crystallization peaks of the thermogram at 2°C per minute were analyzed to determine the relative nucleation performance. 34-36 The nucleation efficiency percentage for each blended sample is given by the following formula.

[0152] Where T c,NA It is the peak crystallization temperature of the sample containing the nucleating agent, T. c,PHBH It is the peak crystallization temperature of a pure polymer under isotropic melting conditions. 37, 38 And T c,max This represents the maximum crystallization peak temperature of the pure polymer under self-initiated crystallization conditions. While previous analyses determined the latter two temperatures at a conventional DSC slack rate of 10 °C, these conditions were not applicable to evaluating the PHBH used in this study because PHBH does not crystallize from isotropic melt conditions before reaching its glass transition temperature (approximately 0 °C) upon cooling at 10 °C / min. Under a slower cooling rate of 2 °C / min, pure PHBH crystallized from isotropic melt conditions at 58.46 °C. The maximum value was found by cooling molten PHBH samples melted at different temperatures within the self-initiated crystallization scheme, thus establishing Tmax. c,max (109.21℃), the maximum value corresponds to 152℃. At or below 1.0 w / w%, all derivatives reach their maximum efficiency and exhibit very good nucleation performance (approximately 60-80% efficiency). Figures 3A-3DMethyl orotate reached its maximum efficiency at 1.0 w / w% (67%), ethyl orotate at 0.2 w / w% (76%), propyl orotate at 0.8% (69%), and butyl orotate at 0.6% (72%). However, above 1.0 w / w% concentration, the performance of orotate derivatives fell into two categories: those with stable and unstable concentration-dependent properties. Regardless of concentration, stable methyl and propyl derivatives maintained nucleation efficiencies greater than 40%, while unstable ethyl and butyl derivatives showed significantly decreased performance at higher concentrations. The nucleation performance of ethyl orotate became negative at approximately 2.0 w / w% concentration, indicating that its nucleation behavior was even worse than that of pure PHBH. The performance decline of butyl orotate was similar to that of ethyl orotate; however, its nucleation performance never fell below 0% efficiency. Ethyl orotate partially recovers its performance at concentrations above approximately 2.2 w / w%, achieving 20-30% efficiency at concentrations of 3-5 w / w%. Butyl orotate shows a slight increase in performance at higher concentrations, but like other orot esters, it never regains its optimal low-concentration efficiency. Importantly, while some concentrations of different derivatives nucleate better than others, no single derivative reaches a concentration close to the nucleation efficiency (99.0%) of orotate. Table 1 provides the nucleation efficiencies of all materials at all concentrations for reference. Table 1: Nucleation peak temperature and efficiency of methyl orotic acid, ethyl orotic acid, propyl orotic acid, and butyl orotic acid at all tested concentrations.

[0153] Polarization optical microscopy

[0154] To further analyze the concentration-dependent nucleation behavior of orotic acid derivatives in PHBH, polarized optical microscopy (POM) was used to visually confirm crystallization activity. Figures 4A-4D After cooling from the isotropic melt to 50°C at a rate of 30°C / min, different combinations of orotic esters and concentrations in PHBH resulted in varying spherulite size, shape, and density. The optimal concentration, as measured by DSC, exhibited closely packed small spherulites that completely or almost completely covered the visible area. In contrast, the suboptimal concentrations showed large nucleating agent crystals (e.g., 5.0 w / w% propyl oroticate) or even no signs of nucleation (2.0% ethyl oroticate and butyl oroticate).

[0155] Scanning electron microscopy (SEM)

[0156] Considering the significant differences in nucleation properties among different concentrations of each orot ester nucleating agent, scanning electron microscopy (SEM) was used to observe the crystal morphology in each extruded sample. Figures 5A-5DWhile each sample contained some form of nucleating crystals, their size, quantity, and morphology varied considerably not only between derivative types but also between concentrations. Methyl orotate exhibited the least concentration-dependent morphology, with similarly sized crystals (and mixtures of larger crystals at higher loadings) present at all concentrations, consistent with the relatively stable nucleation properties determined by DSC. Ethyl orotate showed the most extensive variation, with crystal shape varying between the 0.2 w / w% and 2 w / w% samples. Interestingly, the crystal morphology shifted from broad, flat, radially projecting crystals to a “regular” massive crystal phase, more similar to those in the methyl orotate samples. These flat, radially projecting crystals were easily destroyed by high-resolution electron microscopy and therefore difficult to observe more closely. Clearly, the variation in crystal morphology is the primary cause of the significant differences in nucleation properties observed between the 0.2 w / w% and 5 w / w% ethyl orotate samples. Further inference suggests that although no visible crystal growth or nucleation was observed in the 2 w / w% SEM experiments, the presence of ethyl orotate crystals in the 2 w / w% SEM samples indicates that recrystallization of regular ethyl orotate crystals at 2 w / w% must be too slow for nucleation efficiency. Therefore, the presence of 2 w / w% ethyl orotate in molten PHBH is expected to hinder the stacking of PHBH polymer chains, resulting in an inhibited (i.e., negatively efficient) crystallization rate. Higher concentrations of ethyl orotate are expected to undergo more rapid bulk recrystallization, re-establishing nucleation properties (albeit less than radial crystal types), as observed in DSC. Propyl orotate behaves similarly to methyl orotate; however, the presence of much larger crystals (>50 μm) in the 5 w / w% samples may indicate reduced solubility in PHBH compared to methyl orotate, but still confirms the similar performance of propyl orotate compared to ethyl orotate. Butyl orotate exhibits behavior similar to ethyl orotate, producing radial structures at low concentrations but not at higher concentrations.

[0157] Crystal structure determined

[0158] As observed by SEM, the large crystals of each orotic acid derivative exhibit distinct shapes and aspect ratios. X-ray crystallography analysis revealed the complete crystal structures of each compound. Ethyl oroticate, propyl oroticate, and butyl oroticate crystals are all composed of independent molecular sheets bonded by hydrogen atoms through imide hydrogen and carbonyl oxygen atoms. These sheets are parallel to (…). The (120) plane (ethyl), (120) plane (propyl), and (130) plane (butyl) have d-spacings of 3.34 Å, 3.37 Å, and 3.01 Å, respectively. In contrast, the methyl derivative consists of two sets of interconnected vertical sheets, each parallel to (210) and (…). Furthermore, the d-spacing of both sets of interconnected vertical sheets is 3.22 Å. The alkyl chains of the methyl and butyl derivative molecules remain in-plane; however, the alkyl chain of one molecule of the asymmetric unit of ethyl orotate and the two alkyl chains within the asymmetric unit of butyl orotate are oriented out-of-plane. The molecular orientation within the crystal structure of each material is... Figures 6A-6D As shown in the image.

[0159] Lattice matching and hydrogen bond fitting of orot esters with PHBH

[0160] Table 2 shows the crystal cell sizes of PHBH and orotic acid monohydrate as previously reported. 41, 42 And the orotic esters studied in this study. To rationalize the different nucleation efficiencies of each orotic ester, a lattice-matching method was employed, which involves finding the optimal possible arrangement between the nucleating agent crystal and the nucleating polymer. Previous reports have shown that the crystal structure of orotic acid monohydrate is very close to that of PHB, which explains its superior level of nucleation performance: (001) OA Face and (100) PHBH The lattice matching is excellent, with a very low mismatch rate. Compared to orotic acid, orotic esters show poorer lattice matching with PHBH, which is expected given their reduced nucleation efficiency (Table 3). Butyl oroticate exhibits particularly poor lattice matching, with individual matching dimensions exceeding the critical 15% maximum value explained by Royaler. 43 Regardless of which crystal facet is paired with PHBH. Table 2: Cell data of PHBH, orotic acid monohydrate, and orotic esters in this study. Table 3: Lattice matching of PHBHH with orotic acid and orotic esters.

[0161] It should be emphasized that the embodiments described above in this disclosure are merely examples of possible implementations and are only illustrated for the purpose of clearly understanding the principles of this disclosure. Many variations and modifications can be made to the above embodiments of this disclosure without substantially departing from the spirit and principles of this disclosure. All such modifications and variations are intended to be included within the scope of this disclosure. References (1) Eraslan, K.; Aversa, C.; Nofar, M.; Barletta, M.; Gisario, A.; Salehiyan, R.; Goksu, YA Poly(3-hydroxybutyrate-co-3-hydroxyhexanoate)(PHBH): Synthesis, properties, and applications - A Review. European Polymer Journal ( European Polymer Journal )》2022, 167 , 111044. (2) Koller, M.; Mukherjee, A. A new wave of industrialization of PHA biopolyesters. *Bioengineering* Bioengineering )》2022, 9 (2),74. 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Claims

1. A polymer composition comprising a poly(hydroxyalkanoate) and a nucleating agent, wherein the nucleating agent comprises an ester of orotic acid, an amide of orotic acid, or a combination thereof.

2. The composition according to claim 1, wherein the orotic acid ester is of formula I. Where R 1 It is a branched or straight-chain C1 to C10 alkyl, C3 to C7 cycloalkyl or aryl.

3. The composition according to claim 2, wherein R 1 The acid is methyl, ethyl, propyl, or butyl.

4. The composition according to claim 1, wherein the orotic acid amide is of formula II. Where R 2 It is hydrogen, branched or straight-chain C1 to C10 alkyl, C3 to C7 cycloalkyl or aryl.

5. The composition according to claim 4, wherein R 2 It is hydrogen.

6. The composition according to claim 4, wherein R 2 It is cyclohexyl.

7. The composition according to claim 4, wherein R 2 It is either a substituted or unsubstituted phenyl group.

8. The composition according to claim 1, wherein the nucleating agent comprises about 0.01% by weight to about 10.0% by weight of the polymer composition.

9. The composition of claim 1, wherein the nucleating agent is methyl orotic acid, ethyl orotic acid, propyl orotic acid, or butyl orotic acid, and the nucleating agent accounts for about 0.01% to about 1.0% by weight of the polymer composition.

10. The composition of claim 1, wherein the nucleating agent is methyl orotate, and the nucleating agent accounts for about 0.8% to about 1.2% by weight of the polymer composition.

11. The composition of claim 1, wherein the nucleating agent is ethyl orotate, and the nucleating agent comprises about 0.1% to about 0.3% by weight of the polymer composition.

12. The composition of claim 1, wherein the nucleating agent is propyl orotate, and the nucleating agent accounts for about 0.6% to about 1.0% by weight of the polymer composition.

13. The composition of claim 1, wherein the nucleating agent is butyl orotate, and the nucleating agent accounts for about 0.4% to about 0.8% by weight of the polymer composition.

14. The composition according to claim 1, wherein the nucleating agent is moltenly soluble in the poly(hydroxyalkanoate).

15. The composition of claim 1, wherein the poly(hydroxyalkanoate) is a copolymer of 3-hydroxybutyrate and at least one comonomer selected from the group consisting of: 3-hydroxypropionate, 3-hydroxyvalerate, 3-hydroxyhexanoate, 3-hydroxyheptanoate, 3-hydroxyoctanoate, 3-hydroxynonanoate, 3-hydroxydecanoate, 3-hydroxydodecanate, 3-hydroxydodecenoate, 3-hydroxytetradecanoate, 3-hydroxytetradecanoate, 3-hydroxyhexadecanoate, 3-hydroxyoctadecanoate, 3-hydroxy-4-pentenoate, 4-hydroxybutyrate, 4-hydroxyvalerate, 5-hydroxyvalerate, and 6-hydroxyhexanoate.

16. The composition of claim 1, wherein the poly(hydroxyalkanoate) is selected from the group consisting of: poly(3-hydroxybutyrate-co-3-hydroxypropionate), poly(3-hydroxybutyrate-co-4-hydroxybutyrate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxybutyrate-co-3-hydroxyhexanoate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate), and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate-co-3-hydroxycaproate-co-3-hydroxyhexanoate).

17. The composition of claim 1, wherein the poly(hydroxyalkanoate) is a polyhydroxyalkanoate homopolymer selected from the group consisting of: poly(3-hydroxybutyrate), polylactic acid, polyglycolic acid, and poly(4-hydroxybutyrate).

18. The composition of claim 1, wherein the polyhydroxyalkanoate poly(hydroxybutyrate-co-hydroxyhexanoate).

19. A method for crystallizing poly(hydroxyalkanoate), the method comprising: (a) The poly(hydroxyalkanoate) and a first nucleating agent are mixed, wherein the first nucleating agent comprises an ester of orotic acid, an amide of orotic acid, or a combination thereof, to produce a first composition; (b) Heating the first mixture to a temperature above the melting point of the poly(hydroxyalkanoate) for a time sufficient to melt the poly(hydroxyalkanoate) to produce a molten composition; and (c) Cool the molten composition to produce crystalline poly(hydroxyalkanoate).

20. The method of claim 19, wherein during step (b), at least a portion of the first nucleating agent dissolves in the molten composition.

21. The method of claim 19, wherein during step (b), a single-phase solution of the poly(hydroxyalkanoate) and the first nucleating agent is formed, wherein the first nucleating agent is dissolved in the molten poly(hydroxyalkanoate).

22. The method of claim 19, wherein the first nucleating agent has a first melting temperature, wherein in step (b), the poly(hydroxyalkanoate) is melted at a temperature below the first melting temperature to form a single-phase solution of the poly(hydroxyalkanoate) and the first nucleating agent.

23. The method of claim 19, wherein step (b) comprises heating the poly(hydroxyalkanoate) and the first nucleating agent to a temperature below 175°C.

24. The method of claim 19, wherein the first nucleating agent comprises a first ester or amide of orotic acid having a first chemical structure and a second ester or amide of orotic acid having a second chemical structure, wherein the first chemical structure is different from the second chemical structure.

25. The method of claim 19, wherein the first composition further comprises a solid filler or a second nucleating agent, wherein the solid filler or the second nucleating agent cannot be melt-dissolved in the molten composition.

26. The method of claim 19, wherein the first composition does not include a solid filler or a second nucleating agent, wherein the solid filler or the second nucleating agent cannot be melt-dissolved in the molten composition.

27. The method of claim 26, wherein the second nucleating agent is orotic acid.

28. The method of claim 19, wherein in step (b), the first composition is heated from about 30°C to about 80°C, above the melting point of the poly(hydroxyalkanoate).

29. The method of claim 19, wherein in step (b), the first composition is heated from about 0°C to about 225°C for about 2 minutes to about 1 hour.

30. The method of claim 19, wherein in step (c), the molten composition is cooled to about 60°C to about 110°C for about 1 minute to about 1 hour.

31. The method of claim 19, wherein the first composition is extruded during step (b).

32. The method of claim 31, wherein the first composition is extruded into a sheet, film, or fiber.

33. The method of claim 19, wherein during step (b), the first composition is injected into a mold.

34. The method of claim 33, wherein after the first composition is injected into the mold to form the molten composition, the molten composition is foamed.

35. The method of claim 34, wherein the first composition further comprises a foaming agent.

36. The method of claim 35, wherein the foaming agent comprises a supercritical fluid foaming agent.

37. A crystalline poly(hydroxyalkanoate) produced by the method according to claim 19.

38. A method for extruding poly(hydroxyalkanoate), the method comprising: (a) Forming a first composition comprising molten poly(hydroxyalkanoate) and a first nucleating agent, wherein the first nucleating agent comprises an ester or orotic acid, an amide of orotic acid, or a combination thereof; (b) Extruding the first composition to produce an extruded composition; and (c) Lowering the temperature of the extruded composition to initiate crystallization of the molten poly(hydroxyalkanoate) and to solidify the extruded composition.

39. A method for injection molding poly(hydroxyalkanoate), the method comprising: (a) Forming a first composition comprising molten poly(hydroxyalkanoate) and a first nucleating agent, wherein the first nucleating agent comprises an ester of orotic acid, an amide of orotic acid, or a combination thereof; (b) Injecting the first composition into a mold to produce an injected molten composition; (c) Reducing the temperature of the injected molten composition in the mold, reducing the pressure in the mold, or a combination thereof, to initiate crystallization of the poly(hydroxyalkanoate) in the injected molten composition and to solidify the injected molten composition in the mold; and (d) Remove the cured composition from the mold.

40. The method of claim 19, wherein the nucleation efficiency of the method is about 60% to about 80%.

41. An article of manufacture made by the method according to claim 38 or 39.

42. A compound of formula I Where R 1 It is a branched or straight-chain C1 to C10 alkyl, C3 to C7 cycloalkyl or aryl.

43. A compound of formula II Where R 2 It is hydrogen, branched or straight-chain C1 to C10 alkyl, C3 to C7 cycloalkyl or aryl.

44. A molten polymer composition comprising a molten poly(hydroxyalkanoate) and a nucleating agent, wherein the nucleating agent comprises an ester of orotic acid, an amide of orotic acid, or a combination thereof, wherein at least a portion of the nucleating agent is dissolved in the molten poly(hydroxyalkanoate).

45. The molten polymer composition of claim 44, wherein the molten composition comprises a single-phase solution of the molten poly(hydroxyalkanoate) and the nucleating agent, wherein the nucleating agent is dissolved in the molten poly(hydroxyalkanoate).

46. ​​The molten polymer composition according to claim 44 or 45, wherein the nucleating agent is completely dissolved in the molten poly(hydroxyalkanoate).

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