Use of orotic acid esters and amides as nucleators for poly(hydroxyalkenoates)

Abstract

Described herein are orotic acid esters and amides as nucleators for crystallizing molten poly(hydroxyalkanoates). The orotic acid esters and amides are soluble in the molten poly(hydroxyalkanoates) and have high nucleating efficiencies. The use of the orotic acid esters and amides described herein provide several advantages with respect to producing articles composed of thepoly(hydroxyalkanoates).

Description

USE OF OROTIC ACID ESTERS AND AMIDES AS NUCLEATORS FOR POLY(HYDROXYALKENOATES)CROSS-REFERENCE TO RELATED APPLICATIONS

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

[0002] Poly(hydroxyalkanoates) (PHAs) are enormously versatile, and as many as 100 different PHA structures have been identified. PHA structures can vary in two ways. For example, poly(hydroxybutyrate-co-hydroxyhexanoate) (PHBH) is a biologically degradable copolymer of 3-hydroxy butyric acid (3HB) and 3-hydroxyhexanoic acid (3HHx) in the poly(hydroxyalkanoate) PHA family that exhibits improved processability and materials properties compared to its predecessor, poly(hydroxybutyrate) (PHB).1Despite its vast potential as a means of offsetting the world’s reliance on fossil fuels for single-use commodities, PHBH implementation (along with all other PHAs) has been slow: PHAs are impeded by their high production costs, pronounced physical aging, and poor crystallization kinetics.2 3While improved economy-of-scale have begun to decrease production costs,4and advancements in formulation have worked to reduce the effects of physical aging,5PHAs continue to face challenges in crystallization rate.

[0003] PHBH (and all other PHAs) are being considered for high throughput, low margin applications such as single-use plastic items,6which require rapid manufacture. Long injection mold dwell times, slow production speeds, and long cycle times are therefore antithetical to industry demands. Slow crystallization speeds have traditionally been improved by addition of small crystals into the polymer which increase crystallization temperature and crystallization speed by providing nucleation sites that facilitate the polymer phase change at higher temperatures.7 8SUMMARY

[0004] Described herein are orotic acid esters and amides as nucleators for crystallizing molten poly(hydroxyalkanoates). The orotic acid esters and amides are soluble in the molten poly(hydroxyalkanoates) and have high nucleating efficiencies. The use of the orotic acidesters and amides described herein provide several advantages with respect to producing articles composed of thepoly(hydroxyalkanoates).

[0005] Other compositions, apparatus, methods, features, and advantages will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional compositions, apparatus, methods, features and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Further aspects of the present disclosure will be more readily appreciated upon review of the detailed description of its various embodiments, described below, when taken in conjunction with the accompanying drawings.

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

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

[0009] Figures 3A-3D show nucleation efficiencies of (a) methyl orotate, (b) ethyl orotate, (c) propyl orotate, and (d) butyl orotate at different loadings in PHBH.

[0010] Figures 4A-4D show POM images of (a) methyl orotate, (b) ethyl orotate, (c) propyl orotate, and (d) butyl orotate in PHBH at 50°C, at varying concentrations.

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

[0012] Figures 6A-6D show molecular orientations of (a) methyl orotate, (b) ethyl orotate, (c) propyl orotate, and (d) butyl orotate within their crystalline unit cells.

[0013] The drawings illustrate only example embodiments and are therefore not to be considered limiting of the scope described herein, as other equally effective embodiments are within the scope and spirit of this disclosure. The elements and features shown in the drawings are not necessarily drawn to scale, emphasis instead being placed upon clearly illustrating the principles of the embodiments. Additionally, certain dimensions may be exaggerated to help visually convey certain principles. In the drawings, similar reference numerals between figures designate like or corresponding, but not necessarily the same, elements.DETAILED DESCRIPTION

[0014] Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not 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. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0015] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0016] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0017] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain 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 which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0019] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

[0020] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, 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 belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0021] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.Definitions

[0022] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” “having,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of’ and “consisting of.” Similarly, the term “consisting essentially of’ is intended to include examples encompassed by the term “consisting of.

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

[0024] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, andthat each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0025] When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “xto y” includes the range from ‘x’ to ‘y’ as well as the range greater than x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about x’ to about ‘y’”.

[0026] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1 % to about 5%, but also include individual values (e.g., about 1 %, about 2%, about 3%, and about 4%) and the sub-ranges (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 sub-ranges) within the indicated range.

[0027] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonablydetermined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0028] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0029] Disclosed are the components to be used to prepare the compositions disclosed herein as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B- D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of theseadditional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0030] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.

[0031] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance and instances where it does not.

[0032] The term “ester” as used herein is represented by the formula -C(O)OA1, where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0033] The term “amide” as used herein is represented by the formula -C(O)NHA1, where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0034] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, f-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, CI- 07 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.

[0035] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a singlehalide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

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

[0037] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with 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, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl. Fused aryl groups including, but not limited to, indene and naphthalene groups are also contemplated.

[0038] The term “heteroaryl” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1 ,2-b]pyridazinyl, imidazo[1 ,2- a]pyrazinyl, benzo[c][1 ,2,5]thiadiazolyl, benzo[c][1 ,2,5]oxadiazolyl, and py ri d o [2, 3- b] pyrazinyl.

[0039] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A1A2)C=C(A3A4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated 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, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0040] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl 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, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0041] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or 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, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.Orotic Acid Esters and Amides and Methods for Making and Using the Same

[0042] Described herein are orotic acid esters and amides as nucleators for crystallizing molten poly(hydroxyalkanoates). The orotic acid esters and amides are soluble in the molten poly(hydroxyalkanoates) and have high nucleating efficiencies. The use of the orotic acid esters and amides described herein provide several advantages with respect to 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 exceptionally rare. Melt soluble nucleating agents are desirable because they 1) provide a homogeneous melt which is more conducive to the production of small extrudates (i.e. films, fibers, etc.) and 2) because they ensure their own uniform distribution during shear processing and therefore generate more consistent products. The orotic acid esters and amides described herein address this need.

[0044] In one aspect, the orotic acid esters and amides described herein are completely soluble in molten poly(hydroxyalkanoates). In another aspect, the orotic acid esters and amides described herein are completely soluble in molten poly(hydroxyalkanoates) when the orotic acid esters and amides are up to 10 weight percent of the molten composition. The solubility of the orotic acid esters and amides described herein can be determined by techniques known in the art. In one aspect, the molten composition composed of the poly(hydroxyalkanoate) and the orotic acid ester or amide can be visually inspected to determine if there are any solid particles of the orotic acid ester or amide.

[0045] In one aspect, the ester of orotic is formula Iwherein R1is branched or straight chain C1 to C10 alkyl group, a C3 to C7 cycloalkyl group, or an aryl group.

[0046] In one aspect, R1in formula I is methyl, ethyl, propyl, or butyl. In one aspect, the ester of orotic acid having the formula I is the reaction product between orotic acid and an alcohol R1OH, where R1is defined above (e.g., methanol, ethanol, propanol, butanol, etc.). The Examples provide non-limiting procedures for making and purifying the esters of orotic acid as described herein.

[0047] In another aspect, the amide of orotic is formula IIwherein R2is hydrogen, a branched or straight chain C1 to C10 alkyl group, a C3 to C7 cycloalkyl group, or an aryl group.

[0048] In one aspect, R2in formula II is hydrogen. In another aspect, R2in formula II is cyclohexyl. In another aspect, R2in formula II is substituted or unsubstituted phenyl. In one aspect, the ester of orotic acid having the formula II is the reaction product between orotic acid and an amine R2NH2, where R2is defined above. The Examples provide non-limiting procedures for making and purifying the amides of orotic acid as described herein.

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

[0050] In one aspect, the method for crystallizing a poly(hydroxyalkanoate) comprises(a) admixing the 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 to produce a first composition;(b) heating the first mixture above the melting point of the poly(hydroxyalkanoate) for a sufficient time to melt the poly(hydroxyalkanoate) to produce a molten composition; and(c) cooling the molten composition to produce a crystallized poly(hydroxyalkanoate).

[0051] Step (a) involves admixing the poly(hydroxyalkanoate) and the first nucleating agent such that the first nucleating agent is evenly 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 certain aspects, the first nucleating agent can include two or more different compounds having the structure in formulae I and II above. In one aspect, 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. In one aspect, the nucleating agent can include two different orotic acid esters having the formula I. In another aspect, the nucleating agent can include two different orotic acid amides having the formula II. In another aspect, the nucleating agent can include a combination of an orotic acid ester and amide having the formulae I and II, respectively.

[0053] In certain aspects, additional components can be added to the poly(hydroxyalkanoate) and the first nucleating agent. In one aspect, a solid filler or a second nucleating agent can be added to the poly(hydroxyalkanoate) and the first nucleating agent, wherein the solid filler or second nucleating agent is not melt soluble in the molten composition. In one aspect, the second melt insoluble nucleating agent can be orotic acid. In other aspect, no fillers or other melt insoluble materials are 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. In one aspect, the first nucleating agent is from about 0.01 weight percent to about 10.0 weight percent of the polymeric composition composed of the poly(hydroxyalkanoate)and the first nucleating agent. In another aspect, the first nucleating agent is about 0.01 weight percent, 0.05 weight percent, 0.1 weight percent, 0.2 weight percent, 0.3 weight percent, 0.4 weight percent, 0.5 weight percent, 0.6 weight percent, 0.7 weight percent, 0.8 weight percent, 0.9 weight percent, 1.0 weight percent, 1.5 weight percent, 2.0 weight percent, 2.5 weight percent, 3.0 weight percent, 3.5 weight percent, 4.0 weight percent, 5.0 weight percent, 6.0 weight percent, 7.0 weight percent, 8.0 weight percent, 9.0 weight percent, or 10.0 weight percent, where any value can be a lower and upper endpoint of a range (e.g., 0.2 weight percent to 1 .5 weight percent).

[0055] In one aspect, when the first nucleating agent is methyl orotate, ethyl orotate, propyl orotate, or butyl orotate, the first nucleating agent is from about 0.01 weight percent to about 1.0 weight percent of the polymeric composition, or 0.01 weight percent, 0.05 weight percent, 0.1 weight percent, 0.2 weight percent, 0.3 weight percent, 0.4 weight percent, 0.5 weight percent, 0.6 weight percent, 0.7 weight percent, 0.8 weight percent, 0.9 weight percent, or 1.0 weight percent, where any value can be a lower and upper endpoint of a range (e.g., 0.2 weight percent to 0.8 weight percent).

[0056] In one aspect, when the first nucleating agent is methyl orotate (R1is methyl in formula I), the first nucleating agent is from about 0.8 weight percent to about 1.2 weight percent of the polymeric composition, or 0.8 weight percent, 0.85 weight percent, 0.9 weight percent, 0.95 weight percent, 1.0 weight percent, 1.05 weight percent, 1.10 weight percent, 1.15 weight percent, or 1 .2 weight percent, where any value can be a lower and upper endpoint of a range (e.g., 0.85 weight percent to 1.15 weight percent).

[0057] In one aspect, when the first nucleating agent is ethyl orotate (R1is ethyl in formula I), the first nucleating agent is from about 0.1 weight percent to about 0.3 weight percent of the polymeric composition, or 0.1 weight percent, 0.15 weight percent, 0.2 weight percent, 0.25 weight percent, or 0.3 weight percent, where any value can be a lower and upper endpoint of a range (e.g., 0.85 weight percent to 1.15 weight percent).

[0058] In one aspect, when the first nucleating agent is propyl orotate (R1is propyl in formula I), the first nucleating agent is from about 0.6 weight percent to about 1.0 weight percent of the polymeric composition, or 0.6 weight percent, 0.65 weight percent, 0.7 weight percent, 0.75 weight percent, 0.80 weight percent, 0.85 weight percent, 0.9 weight percent, 0.95 weight percent, or 1.0 weight percent, where any value can be a lower and upper endpoint of a range (e.g., 0.65 weight percent to 0.85 weight percent).

[0059] In one aspect, when the first nucleating agent is butyl orotate (R1is butyl in formula I), the first nucleating agent is from about 0.4 weight percent to about 0.8 weight percent ofthe polymeric composition, or 0.4 weight percent, 0.45 weight percent, 0.5 weight percent, 0.55 weight percent, 0.6 weight percent, 0.65 weight percent, 0.7 weight percent, 0.75 weight percent, or 0.8 weight percent, where any value can be a lower and upper endpoint of a range (e.g., 0.45 weight percent to 0.65 weight percent).

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

[0061] In one aspect, the poly(hydroxyalkanoate) is a copolymer of 3-hydroxybutyrate and at least one co-monomer selected from the group consisting of 3-hydroxypropionate, 3- hydroxyvalerate, 3-hydroxyhexanoate, 3-hydroxyheptanoate, 3-hydroxyoctanoate, 3- hydroxynonaoate, 3-hydroxydecanoate, 3-hydroxydodecanoate, 3-hydroxydodecenoate, 3- hydroxytetradecanoate, 3-hydroxyhexadecanoate, 3-hydroxyoctadecanoate, 3-hydroxy-4- pentenoate, 4-hydroxybutyrate, 4-hydroxyvalerate, 5-hydroxyvalerate, and 6- hydroxyhexanoate.

[0062] In one aspect, 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-hydroxyoctanoate-co-3-hydroxydecanoate-co-3- hydroxydodecanotate-co-3-hydroxydodecenotate).

[0063] Depending upon the application or the article to be produced, two or more different poly(hydroxyalkanoates) can be combined with the nucleators described herein. The molecular weight of the of the poly(hydroxyalkanoate) can vary. In one aspect, the molecular weight of the poly(hydroxyalkanoate) is from about 10,000 to about 3,000,000. in another aspect, the molecular weight of the poly(hydroxyalkanoate) is from about 300,000 to about 1 ,000,000.

[0064] After the poly(hydroxyalkanoate) and the nucleator described have been mixed, the resulting polymeric composition is heated above the melting point of the poly(hydroxyalkanoate) for a sufficient time to melt the poly(hydroxyalkanoate) to produce a molten polymeric composition.

[0065] The temperature and time needed to produce completely melt the poly(hydroxyalkanoate) to produce a molten polymeric composition composed of the nucleating agent can vary depending upon the selection of the poly(hydroxyalkanoate) andthe method for heating the poly(hydroxyalkanoate). During the heating process, the nucleating agents described herein will be solubilized in the molten poly(hydroxyalkanoate). In one aspect, melting the poly(hydroxyalkanoate) with the nucleating agents described herein produces a single-phase solution of the poly(hydroxyalkanoate) and the nucleating agent at a temperature below the melting temperature of the nucleating agent.

[0066] The use of the nucleating agents described herein requires lower melting temperatures compared to other nucleating agents known in the art. For example, pentaerythritol requires temperatures at about 180 °C to solubilize in poly(hydroxyalkanoates). In one aspect, the poly(hydroxyalkanoate) and nucleating agent described herein are heated to a temperature of less than 175 °C.

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

[0068] In one aspect, the molten polymeric composition composed of the poly(hydroxyalkanoate) with nucleating agent described herein can be produced by an extruder. The extruder can have a motor to turn a screw inside the extruder. Extruder may be a single screw or twin screws made of individual elements of various sizes and pitches appropriate for mixing or kneading the specific materials used. In some examples, the extruder has a twin screw. The extruder can produce a number of different articles including, but not limited to, sheets, films, or fibers.

[0069] The poly(hydroxyalkanoate) with nucleating agent described herein and optional components (e.g., fillers) are added into the extruder through one or more port. The various components can be added as a melt or as appropriately-sized solid particles, for example chips or pellets, that are melted in section as they are mixed in the barrel of the extruder. The contents of the extruder can be heated to melt the composition.

[0070] In certain aspects, a blowing agent can be added to produce poly(hydroxyalkanoate) foams. In one aspect, a supercritical fluid can be added into the melt as a physical blowing agent. In particular examples, the poly(hydroxyalkanoate) foam is prepared by using a physical blowing agent which foams the composition after it exits theextruder, and the poly(hydroxyalkanoate) foam is thus substantially free of a chemical blowing agent or decomposition product thereof.

[0071] In another aspect, if a chemical blowing agent is used, the processing (melting) temperature used can be sufficiently below the temperature that would trigger the blowing agent. In order to foam the composition, the temperature near the exit of the extruder can be increased to a temperature close to or at the triggering temperature of a chemical blowing agent, thereby producing a chemically foamed poly(hydroxyalkanoate) foam as the composition exits the extruder (e.g., as the composition is injected into an injection mold).

[0072] Alternatively or in addition, a physical blowing agent can be used for foam the composition to form a physically foamed poly(hydroxyalkanoate) foam, or a physically and chemically foamed poly(hydroxyalkanoate) foam. For example, a supercritical fluid such as supercritical carbon dioxide or supercritical nitrogen can be mixed with the molten polymeric composition in the barrel of the extruder to form a single-phase solution. As the single-phase solution exits the extruder, the pressure drop between the higher pressure in the extruder and the lower pressure outside the extruder causes the supercritical fluid to transition to the gas phase and foam the molten polymeric composition.

[0073] In another aspect, molded articles composed of a poly(hydroxyalkanoate) and nucleating described herein can be produced by injection molding. The injection molding can use a screw-type injector that allows for maintaining and controlling the pressure in the injector barrel, where the molten polymeric composition is injected into a mold. In certain aspects, a blowing agent as described above can be mixed into the molten polymeric composition within the injection barrel and then injected into the mold. For example, the injection molding machine can allow metering and delivering a supercritical fluid such as carbon dioxide or nitrogen into the composition prior to injection. The supercritical fluid can then expand to create cell nuclei to form the physical foam within the mold.

[0074] Once the article composed of molten polymeric composition composed of the poly(hydroxyalkanoate) and nucleating described herein is produced, the article is cooled to initiate crystallization of the molten poly(hydroxyalkanoate) and solidify the polymer in the article. In one aspect, the melted composition is cooled to about 60 °C to about 110 °C for about 1 minute to about 1 hour to crystallize the poly(hydroxyalkanoate).

[0075] The nucleating agents described herein have a high nucleation efficiency. Not wishing to be bound by theory, the melt-solubility of the nucleating agents described herein in molten poly(hydroxyalkanoates) accounts for the increased nucleation efficiency. In one aspect, the nucleating agents described herein have a nucleating efficiency of about 60% toabout 80%. Methods for calculating the nucleation efficiency are provided in the Examples. Thus, the use of the nucleating agents described herein provides an efficient and cost-effective means for producing poly(hydroxyalkanoate) articles.Aspects

[0076] Aspect 1 . A polymeric 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 of Aspect 1 , wherein the ester of orotic is formula Iwherein R1is branched or straight chain C1 to C10 alkyl group, a C3 to C7 cycloalkyl group, or an aryl group.

[0078] Aspect 3. The composition of Aspect 2, wherein R1acid is methyl, ethyl, propyl, ot butyl.

[0079] Aspect 4. The composition of Aspect 1 , wherein the amide of orotic is formula IIwherein R2is hydrogen, a branched or straight chain C1 to C10 alkyl group, a C3 to C7 cycloalkyl group, or an aryl group.

[0080] Aspect 5. The composition of Aspect 4, wherein R2is hydrogen.

[0081] Aspect 6. The composition of Aspect 4, wherein R2is cyclohexyl.

[0082] Aspect 7. The composition of Aspect 4, wherein R2is substituted or unsubstituted phenyl.

[0083] Aspect 8. The composition of any one of Aspects 1 -7, wherein the nucleating agent is from about 0.01 weight percent to about 10.0 weight percent of the polymeric composition.

[0084] Aspect 9. The composition of Aspect 1 , wherein the nucleating agent is methyl orotate, ethyl orotate, propyl orotate, or butyl orotate, and the nucleating agent is from about 0.01 weight percent to about 1.0 weight percent of the polymeric composition.

[0085] Aspect 10. The composition of Aspect 1 , wherein the nucleating agent is methyl orotate, and the nucleating agent is from about 0.8 weight percent to about 1 .2 weight percent of the polymeric composition.

[0086] Aspect 11. The composition of Aspect 1 , wherein the nucleating agent is ethyl orotate, and the nucleating agent is from about 0.1 weight percent to about 0.3 weight percent of the polymeric composition.

[0087] Aspect 12. The composition of Aspect 1 , wherein the nucleating agent is propyl orotate, and the nucleating agent is from about 0.6 weight percent to about 1 .0 weight percent of the polymeric composition.

[0088] Aspect 13. The composition of Aspect 1 , wherein the nucleating agent is butyl orotate, and the nucleating agent is from about 0.4 weight percent to about 0.8 weight percent of the polymeric composition.

[0089] Aspect 14. The composition of any one of Aspects 1-13, wherein the nucleating agent is melt-soluble in the poly(hydroxyalkanoate).

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

[0091] Aspect 16. The composition of any one of Aspects 1-14, 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-hydroxyoctanoate-co-3-hydroxydecanoate-co-3- hydroxydodecanotate-co-3-hydroxydodecenotate).

[0092] Aspect 17. The composition of any one of Aspects 1-14, 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 of any one of Aspects 1-14, wherein the polyhydroxyalkanoate poly(hydroxybutyrate-co-hydroxyhexanoate).

[0094] Aspect 19. A method for crystallizing a poly(hydroxyalkanoate), the method comprising(a) admixing the 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 to produce a first composition;(b) heating the first mixture above the melting point of the poly(hydroxyalkanoate) for a sufficient time to melt the poly(hydroxyalkanoate) to produce a molten composition; and(c) cooling the molten composition to produce a crystallized poly(hydroxyalkanoate).

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

[0096] Aspect 21. The method of Aspect 19, wherein during step (b), forming a singlephase solution of the poly(hydroxyalkanoate) and the first nucleating agent, wherein the first nucleating agent is dissolved in the molten poly(hydroxyalkanoate).

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

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

[0099] Aspect 24. The method of any one of Aspects 19-22, 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 of any one of Aspects 19-24, wherein the first composition further comprises a solid filler or a second nucleating agent, wherein the solid filler or second nucleating agent is not melt soluble in the molten composition.

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

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

[0103] Aspect 28. The method of any one of Aspects 19-26, 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 of any one of Aspects 19-26, 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 of any one of Aspects 19-28, wherein in step (c), the melted composition is cooled to about 60 °C to about 110 °C for about 1 minute to about 1 hour.

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

[0107] Aspect 32. The method of Aspect 31 , wherein the first composition is extruded as a sheet, film, or fiber.

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

[0109] Aspect 34. The method of Aspect 33, wherein after injecting the first composition into the mold to form the molten composition, foaming the molten composition.

[0110] Aspect 35. The method of Aspect 34, wherein the first composition further comprises a blowing agent.

[0111] Aspect 36. The method of Aspect 35, wherein the blowing agent comprises a supercritical fluid blowing agent.

[0112] Aspect 37. A crystallized poly(hydroxyalkanoate) produced by the method of any one of Aspects 19-36.

[0113] Aspect 38. A method of extruding a poly(hydroxyalkanoate), 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 conposition; and(c) decreasing a temperature of the extruded composition to initiate crystallization of the molten poly(hydroxyalkanoate) and solidify the extruded composition.

[0114] Aspect 39. A method of injection molding a poly(hydroxyalkanoate), 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) decreasing a temperature of the injected molten composition in the mold, decreasing a 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) removing the solidified composition from the mold.

[0115] Aspect 40. The method of any one of Aspects 19-39, wherein the method has a nucleation efficiency of about 60% to about 80%.

[0116] Aspect 41. An article made by the method of Aspect 38 or 39.

[0117] Aspect 42. A compound of formula Iwherein R1is branched or straight chain C1 to C10 alkyl group, a C3 to C7 cycloalkyl group, or an aryl group.

[0118] Aspect 43. A compound of formula IIwherein R2is hydrogen, a branched or straight chain C1 to C10 alkyl group, a C3 to C7 cycloalkyl group, or an aryl group.

[0119] Aspect 44. A molten polymeric composition comprising 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 polymeric composition of 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 polymeric composition of Aspect 44 or 45, wherein the nucleating agent is completely dissolved in the molten poly(hydroxyalkanoate).EXAMPLES

[0122] Now having described the embodiments of the disclosure, in general, the examples describe some additional embodiments. While embodiments of the present disclosure are described in connection with the example and the corresponding text and figures, there is no intent to limit embodiments of the disclosure to these descriptions. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of embodiments of the present disclosure.MATERIALS AND METHODS

[0123] Materials

[0124] 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 priorto use to remove associated water. Methanol, ethanol,propanol, butanol, sulfuric acid, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), dimethyl formamide (DMF), and ethyl iodide were all purchased from Sigma Aldrich and used as supplied. Methyl, propyl, and butyl orotates were synthesized via Fisher Esterification with very good to excellent yields (87-96%), while ethyl orotate proved unreactive. Instead, ethyl orotate was afforded via an alternative, previously published route with a very good yield (85%).31

[0125] General Synthesis of Orotate Esters through Fisher Esterification

[0126] 12.5 g of anhydrous orotic acid were added to a 2L, single neck flask followed by1 kg of the corresponding alcohol. 12.5 mL of concentrated sulfuric acid were added. The heterogenous mixture was heated under reflux until all solids were dissolved. The solvent was reduced to approximately 1 / 3 volume through rotary evaporation, and the liquid was cooled to -20°C. The precipitated solids were collected through filtration and washed with the cooled corresponding alcohol. The mother liquor was kept at -20°C for several days, and a second crop of crystals was collected via filtration followed by washing with the corresponding alcohol. The filtrates were dried under vacuum at 60°C for 24h.

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

[0128] The general procedure was followed. The reaction became homogenous after a 5- day reflux. The combined yield of the first and second crops was 12.0 g (88%).1H NMR (600 MHz, CDCI3) 6 11.40 (s, 1 H), 11.14 (s, 1 H), 6.05 (s, 1H), 3.85 (s, 3H).

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

[0130] The general procedure was followed. The reaction became homogenous after a 3- day reflux. The combined yield of the first and second crops was 15.2 g (96%).1H NMR (600 MHz, CDCI3) 5 11.40 (s, 1H), 11.15 (s, 1 H), 6.05 (s, 1 H), 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] The general procedure was followed. The reaction became homogenous after an 18 h. reflux. The combined yield of the first and second crops was14.8 g (87%).1H NMR (600 MHz, CDCI3) 5 11.40 (s, 1H), 11.15 (s, 1 H), 6.05 (s, 1 H), 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 Fisher Esterification of orotates was applied to the synthesis of ethyl 2,6-dioxo-1 ,2,3,6-tetrahydropyrimidine-4-carboxylate. However, even after 7 days of reflux, incomplete conversion was observed both empirically (a persistent heterogenous solution was observed) and through1H NMR monitoring. Instead, a previouslypublished procedure was followed that produced satisfactory results (Patent W02007011065A2, 2006). Briefly, 19.1g of anhydrous orotic acid and 18.6g DBU were dissolved into 35 mL of anhydrous DMF. 22.9 g (1.2 eq.) of ethyl iodide were then added followed by heating to 60°C for 5 h.. 300 mL of cold water was added to the solution to precipitate white crystals which were isolated through filtration. The mother liquor was left to sit at room temperature for 1 day until a second crop of crystals were collected. The combined crops were dried at 60°C for 24 h. to isolate 19.1 g of a white powder (85%).1H NMR (600 MHz, CDCI3) 6 11.40 (s, 1 H), 11.14 (s, 1 H), 6.05 (s, 1H), 4.31 (q, 2H), 1.30 (t, 3H).

[0135] General Synthesis of Orotate Amides

[0136] 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 under a nitrogen atmosphere. The heterogenous mixture was heated to reflux for 3 hours before being cooled to room temperature. The mixture was filtered and the collected solid was washed three times with anhydrous toluene under nitrogen to afford a light tan solid, which was dried in a vacuum desiccator and collected in quantitative yield.

[0137] This solid was then suspended in anhydrous DCM or DMF with 1.0 eq of anhydrous pyridine. 1.2-4.0 eq of the corresponding amine (cyclohexylamine, ammonium hydroxide, aqueous methylamine, or aniline) were then added to the flask dropwise at room temperature. The solution was heated to 40 °C overnight. The precipitated solid was collected via filtration and washed three times with water to yield the orotyl amide.

[0138] Melt Compounding

[0139] Methyl, ethyl, propyl, and butyl orotates were each blended by hand into PHBH powder at varying concentrations ranging from 0.05w / w% to 8.0 w / w% to form 7g samples. The samples were compounded in a Thermo Fisher HAAKE Minilab II conical twin screw extruder at 150°C and 100 rpm screw speed. The samples were allowed to cycle in the extruder for 5 minutes before being extruded into strands fortesting.

[0140] Differential Scanning Calorimetry (DSC)

[0141] Thermal transitions of synthetic products and compounded samples were measured using a TA Discovery 250 Differential Scanning Calorimeter (TA Instruments) under nitrogen. Samples (2-12mg) were enclosed in aluminum pans prior to testing. The melting points of the synthetic products were determined by heating the samples at 10°C min1. For compounded samples, non-isothermal heating procedures began by heating to 200°C at 10°C min1to erase thermal history followed by cooling to -20°C at 10°C min1. These experiments were also repeated, cooling at 2°C min1instead.

[0142] Polarized Optical Microscopy (POM)

[0143] Thin extrudate slices were added to the stage of an Eclipse LV100N POL polarized optical microscope (Nikon, MinatoCity, Tokyo, Japan) equipped with LINK (ver.1 .2.5.1300, Linkam Scientific Instruments, United Kingdom) software. The polarizer and analyzer were both set to 0°,and a 1A (A= 530 nm) tint plate was added in the optical path. Camera settings (exposure, shutter, gain, and white balance) were all set to automatically adjust for optimal picture quality. To evaluate nucleation efficiency of the synthetic products, samples were heated to 200°C at a rate of 150°C / min and held for 1 min, during which the sample was pressed gently to flatten. The samples were then cooled at 30°C / min to 50°C for nucleation observation.

[0144] Crystal Structure Determination

[0145] Colorless crystal specimens of each orotic acid derivative were obtained via solvent recrystallization for X-ray crystallographic analysis. The methyl derivative was recrystallized from methanol (4mg / mL), ethyl from ethanol (14mg / mL), propyl from water (4mg / mL), and butyl from ethanol (10mg / mL). Recrystallization solutions were first heated to boiling, filtered through a 0.2|jm PTFE filter, and allowed to sit undisturbed in tightly capped vials for 7-9 days. The X-ray intensity data were measured at ambient temperature on a Bruker D8 Quest PHOTON 100 CMOS X-ray diffractometer system with Incoatec Microfocus Source (IpS) monochromated Mo Ka radiation (I = 0.71073 A, sealed tube) using phi and omega-scan technique. The data were integrated with the manufacturer's SAINT software and corrected for absorption effects using the multi-scan method (SADABS). Structures were solved and refined using the Bruker SHELXTL software package (Bruker AXS, Madison Wl, USA).32Nonhydrogen atoms were located from successive difference Fourier map calculations. In the final cycles of each refinement, all the non-hydrogen atoms were refined in anisotropic displacement parameters while the hydrogen atoms were calculated and added to their bonded carbon or nitrogen atoms. Crystalline structural alignments were evaluated using VESTA software.33

[0146] Scanning Electron Microscopy (SEM)

[0147] Large crystal morphologies of methyl, ethyl, propyl, and butyl orotates were determined using scanning electron microscopy (FE-SEMI FEI Teneo, Thermo Fisher Scientific, USA). The large crystals were placed onto an aluminum puck covered in doublesided adhesive tape before being sputter coated in 15-20nm of gold / palladium using a LEIA EM ACE200 high-vacuum sputter coater (Wetzlar, Germany). The crystals were then imaged at an accelerating voltage of 10kV. Cryo-fractured surfaces of compounded samples weresimilarly visualized, using an SU9000EA scanning electron microscope (Hitachi, Chiyoda City, Tokyo, Japan). Cryo-fracturing was conducted on POM samples, which were also subsequently mounted and sputter coated.RESULTS AND DISCUSSION

[0148] Thermal Analysis

[0149] The synthesized orotic acid derivatives’ nucleation performances were first evaluated via Differential Scanning Calorimetry (DSC). Figures 1A-1 D show the cooling curve thermograms of the orotate derivatives at the standard rate of 10°C per minute. Each derivative was initially evaluated at 1 ,2,3,4, and 5 w / w%. Additional concentrations were added as needed to comprehensively analyze the significant shifts in the additives’ concentration dependent nucleation behavior. Nucleation of PHBH is evidenced by the presence of crystallization exotherms at varying temperatures, with higher temperatures corresponding to better nucleation performance. Crystallization speed is also qualifiable by the relative peak shape, which varies from broad and flat (indicating slow crystallization) to tall and sharp (indicating rapid crystallization). Given the slow crystallization rate and low temperature of neat PHBH crystallization, rapid crystallizations at high temperatures are considered positive in terms of nucleating agent performance. All samples appear to perform relatively well at low concentrations (at or below 1 .0 w / w%), however some samples show dramatically diminished performance at higher concentrations. Propyl orotate appears the least concentration dependent, with relatively similar performance across a broader range of concentrations. Ethyl orotate, by contrast, performs dramatically differently depending on concentration, with concentrations above 1 .2 w / w% and below 4.0 w / w% showing no nucleation performance. Butyl orotate’s concentration dependence appears like that of ethyl orotate, showing no nucleation performance between 1 .4 w / w% and 3.0 w / w%. Methyl orotate effects nucleation at all evaluated concentrations above 0.2 w / w%, however performance is slightly diminished above 1 .6 w / w%.

[0150] DSC analyses of all nucleators at all concentrations were repeated at a cooling rate of 2°C per minute to establish rate-dependent nucleation performance. The DSC thermograms of compounded samples cooled at 2°C per minute are shown in Figures 2A-2D. Under these conditions, crystallization exotherms appear at higher temperatures than the 10°C per minute samples due to longer residence times at higher temperatures, as the cooling process takes more time. Other than the shifting temperatures, however, the relative performances of each material remain the same. The sharpest crystallization exotherms for each material comprise low concentrations (at or below 1 .0 w / w%) while higher concentrationsshow diminishing performance. The highest nucleation peak temperatures occur 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] Analysis of the 2°C per minute thermograms’ crystallization peaks was performed to establish relative nucleation performance using the percentage nucleation efficiency scale previously proposed by Thierry.34 36The percentage nucleation efficiency for each compounded sample is given by the equation

[0152] Where TC.NA is the crystallization peak temperature of a sample containing nucleating agent, T0,PHBH is the crystallization peak temperature of the neat polymer under isotropic melt conditions,37 38and Tcmax is the maximum crystallization peak temperature of the neat polymer under self-seeding crystallization conditions. While previous analyses establish the latter two temperatures under the conventional DSC ramp rate of 10°C, these conditions are not applicable for evaluating the PHBH used in this work, as it does not crystallize from isotropic melt conditions when cooled at 10°C / min before reaching the glass transition temperature (~0°C). Under the slower, 2°C / min cooling conditions, neat PHBH crystallized from isotropic melt conditions at 58.46°C. The Tc,max (109.21 °C) was established by cooling molten PHBH samples which had been melted at different temperatures within the self-seeding regime to find the maximum, which corresponded to 152°C. At or below 1.0 w / w%, all derivatives reach their maximum efficiency and are capable of very good nucleation performance (~60-80% efficiency) (Figures 3A-3D). Methyl orotate reaches 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%). Above 1.0 w / w% concentration however, the orotic acid derivatives performances divide into two categories: those with stable and unstable concentration dependent performance. The concentration-stable methyl and propyl derivatives maintain greater than 40% nucleation efficiency regardless of concentration, while the unstable ethyl and butyl derivatives show dramatically decreased performance at higher concentrations. Ethyl orotate’s nucleation performance becomes negative at concentrations around 2.0 w / w%, indicating that nucleation behavior is even worse than neat PHBH. Butyl orotate’s performance dips similarly to ethyl orotate’s, however nucleation performance never dips below 0% efficiency. Ethyl orotate’s performance is partially restored at concentrations higher than ~2.2 w / w%, reaching 20-30% efficiency at 3-5 w / w% concentration. Butyl orotate’sperformance modestly increases at higher concentrations, but like the other orotate esters, never regains its optimal, low-concentration efficiency. Importantly, while certain concentrations of different derivatives nucleated better than others, no concentration of any of the derivatives approached that of Orotic Acid (99.0%). All materials’ nucleation efficiencies at all concentrations are available in Table 1 for reference.Table 1 : Nucleation peak temperatures and efficiencies of methyl, ethyl, propyl, and butyl orotates at all tested concentrations.1 w / w% Orotic Acid: 108.7°C peak temperature, 99.0% efficiency- indicates concentrations that were not evaluated

[0153] Polarized 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 to 50°C at a rate of 30°C / minute from the isotropic melt, differing spherulite sizes, shapes, and densities are present in the varying orotate ester and concentration combinations in PHBH. The optimal concentrations via DSC measurement exhibit densely packed, small spherulites which completely or nearly completelyover the visualized areas. Sub-optimal concentrations, by contrast, show large nucleating agent crystals (e.g. 5.0 w / w% propyl orotate) or even no evidence of nucleation (2.0% ethyl and butyl orotates).

[0155] Scanning Electron Microscopy (SEM)

[0156] Given the dramatic differences in nucleation performance between differing concentrations of each orotate ester nucleating agent, scanning electron microscopy (SEM) was employed to visualize the crystal morphologies in each extruded sample (Figures 5A-5D). While each sample contains some form of nucleating crystal, their sizes, numbers, and morphologies vary widely not only between derivative type, but also between concentrations. Methyl orotate shows the least concentration-dependent morphology, with similarly sized crystals (and a mix of larger crystals in higher loadings) present in all concentrations, aligning with the relatively stable nucleation performance as determined by DSC. Ethyl orotate varies the most widely, with varying crystal shapes between 0.2 and 2 w / w% samples. Intriguingly, the crystalline morphology transitions from a wide and flat, radially-projecting crystal to a “regular” bulk crystal phase which is more like those in the methyl orotate samples. These flat, radial crystals were easily destroyed by the electron microscope at high resolutions and were therefore difficult to visualize more closely. It is apparent that the change in crystal morphology is largely responsible for the dramatic difference in nucleation performance observed between 0.2 and 5 w / w% of ethyl orotate. We further reason that, given the presence of ethyl orotate crystals in the 2 w / w% SEM sample despite no visible crystal growth or nucleation in the 2 w / w% SEM experiment, that the recrystallization of the regular ethyl orotate crystals at 2 w / w% must be too slow for nucleation efficiency. It is therefore expected that the presence of 2 w / w% ethyl orotate in molten PHBH hinders the packing of PHBH polymer chains, leading to a repressed (i.e. negative efficiency) crystallization rate. Higher concentrations of ethyl orotate are expected to undergo bulk recrystallization more rapidly, re-enabling nucleation performance (albeit worse than the radial crystal type) as seen in DSC. Propyl orotate behaves similarly to methyl orotate, however much larger crystals (>50 m) were additionally present in the 5 w / w% sample, possibly indicating a decreased solubility in PHBH compared to methyl orotate but nonetheless corroborating the consistent performance of propyl orotate compared to ethyl orotate. Butyl orotate exhibits behavior like that of ethyl orotate, generating radial formations at low concentrations that are not present at higher concentrations.

[0157] Crystal Structure Determination

[0158] Large crystals of each orotic acid derivative showed differing shapes and aspect ratios as seen by SEM. X-ray crystallographic analysis yielded complete crystal structuresolutions for each compound. Ethyl, propyl, and butyl orotate crystals all consist of independent sheets of molecules participating in hydrogen-bonding via their imide hydrogen and carbonyl oxygen atoms. These sheets are oriented parallel to the (221) plane (ethyl), (120) plane (propyl), and (130) plane (butyl) and with d-spacings of 3.34A, 3.37A, and 3.01A, respectively. The methyl derivative, by contrast, consists of two perpendicular sets of interconnected sheets, one each lying parallel to (210) and (210), and both with d-spacings of 3.22A. The alkyl chains of the methyl and butyl derivatives’ molecules remain in-plane, however the alkyl chain of one molecule of the asymmetric unit of ethyl orotate and both alkyl chains within the asymmetric unit of butyl orotate are oriented out of plane. The orientations of molecules within the crystal structures of each material are shown in Figures 6A-6D.

[0159] Lattice Matching and Hydrogen Bond Fitting of Orotate Esters with PHBH

[0160] The crystalline unit cell dimensions for PHBH and orotic acid monohydrate as previously reported,41 42alongside this work’s orotate esters are shown in Table 2. To rationalize the differing nucleation efficiencies of each orotate ester we employed the lattice matching method, which involves finding the best possible alignments between the nucleating agent crystal and the nucleated polymer. Previous reports have shown that the crystal structure of orotic acid monohydrate matches very closely with that of PHB, explaining its exceptional level of nucleation performance: The (001)OAface matches with the (100)PHBH face with very low % mismatch. The orotate esters all share poorer lattice matches with PHBH compared to orotic acid, which is expected given their decreased nucleation efficiency (Table 3). Butyl orotate’s crystal structure match is particularly poor, with a single matching dimension being greater than the critical 15% maximum as explained by royer,43no matter which crystal faces is paired with PHBH.Table 2: Unit cell data for PHBH, orotic acid monohydrate, and this work’s orotate esters.Table 3: Lattice matchings of PHBHH with orotic acid and orotate esters.

[0161] It should be emphasized that the above-described embodiments of the present disclosure are merely possible examples of implementations, and are set forth only for a clear understanding of the principles of the disclosure. Many variations and modifications may be made to the above-described embodiments of the disclosure without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure.REFERENCES(1) Eraslan, K.; Aversa, C.; Nofar, M.; Barletta, M.; Gisario, A.; Salehiyan, R.; Goksu, Y. A. Poly (3-hydroxybutyrate-co-3-hydroxyhexanoate)(PHBH): Synthesis, properties, and applications-A Review. European Polymer Journal 2022, 167, 111044.(2) Koller, M.; Mukherjee, A. A new wave of industrialization of PHA biopolyesters. Bioengineering 2022, 9 (2), 74.(3) Srubar Hi, W.; Wright, Z.; Tsui, A.; Michel, A.; Billington, S.; Frank, C. 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Claims

CLAIMS1. A polymeric 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 of claim 1 , wherein the ester of orotic is formula Iwherein R1is branched or straight chain C1 to C10 alkyl group, a C3 to C7 cycloalkyl group, or an aryl group.

3. The composition of claim 2, wherein R1acid is methyl, ethyl, propyl, ot butyl.

4. The composition of claim 1 , wherein the amide of orotic is formula IIwherein R2is hydrogen, a branched or straight chain C1 to C10 alkyl group, a C3 to C7 cycloalkyl group, or an aryl group.The composition of claim 4, wherein R2is hydrogen.The composition of claim 4, wherein R2is cyclohexyl.The composition of claim 4, wherein R2is substituted or unsubstituted phenyl.The composition of claim 1 , wherein the nucleating agent is from about 0.01 weight percent to about 10.0 weight percent of the polymeric composition.

9. The composition of claim 1 , wherein the nucleating agent is methyl orotate, ethyl orotate, propyl orotate, or butyl orotate, and the nucleating agent is from about 0.01 weight percent to about 1 .0 weight percent of the polymeric composition.

10. The composition of claim 1 , wherein the nucleating agent is methyl orotate, and the nucleating agent is from about 0.8 weight percent to about 1.2 weight percent of the polymeric composition.

11. The composition of claim 1, wherein the nucleating agent is ethyl orotate, and the nucleating agent is from about 0.1 weight percent to about 0.3 weight percent of the polymeric composition.

12. The composition of claim 1 , wherein the nucleating agent is propyl orotate, and the nucleating agent is from about 0.6 weight percent to about 1.0 weight percent of the polymeric composition.

13. The composition of claim 1 , wherein the nucleating agent is butyl orotate, and the nucleating agent is from about 0.4 weight percent to about 0.8 weight percent of the polymeric composition.

14. The composition of claim 1 , wherein the nucleating agent is melt-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 co-monomer selected from the group consisting of 3-hydroxypropionate, 3-hydroxyvalerate, 3-hydroxyhexanoate, 3-hydroxyheptanoate, 3-hydroxyoctanoate, 3-hydroxynonaoate, 3-hydroxydecanoate, 3- hydroxydodecanoate, 3-hydroxydodecenoate, 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-hydroxyoctanoate-co-3- hydroxydecanoate-co-3-hydroxydodecanotate-co-3-hydroxydodecenotate).

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 a poly(hydroxyalkanoate), the method comprising(a) admixing the 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 to produce a first composition;(b) heating the first mixture above the melting point of the poly(hydroxyalkanoate) for a sufficient time to melt the poly(hydroxyalkanoate) to produce a molten composition; and(c) cooling the molten composition to produce a crystallized poly(hydroxyalkanoate).

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

21. The method of claim 19, wherein during step (b), forming a single-phase solution of the poly(hydroxyalkanoate) and the first nucleating agent, 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) melting the poly(hydroxyalkanoate) and forming the single-phase solution of the poly(hydroxyalkanoate) and first nucleating agent at a temperature below the first melting temperature.

23. The method of claim 19, wherein step (b) comprises heating the poly(hydroxyalkanoate) and first nucleating agent to a temperature of less than 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 second nucleating agent is not melt soluble 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 second nucleating agent is not melt soluble 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 about0 °C to about 225 °C for about 2 minutes to about 1 hour.

30. The method of claim 19, wherein in step (c), the melted composition is cooled to about60 °C to about 110 °C for about 1 minute to about 1 hour.

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

32. The method of claim 31 , wherein the first composition is extruded as 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 injecting the first composition into the mold to form the molten composition, foaming the molten composition.

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

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

37. A crystallized poly(hydroxyalkanoate) produced by the method of claim 19.

38. A method of extruding a poly(hydroxyalkanoate), 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 conposition; and(c) decreasing a temperature of the extruded composition to initiate crystallization of the molten poly(hydroxyalkanoate) and solidify the extruded composition.

39. A method of injection molding a poly(hydroxyalkanoate), 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) decreasing a temperature of the injected molten composition in the mold, decreasing a 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) removing the solidified composition from the mold.

40. The method of claim 19, wherein the method has a nucleation efficiency of about 60% to about 80%.41 . An article made by the method of claim 38 or 39.

42. A compound of formula Iwherein R1is branched or straight chain C1 to C10 alkyl group, a C3 to C7 cycloalkyl group, or an aryl group.

43. A compound of formula IIwherein R2is hydrogen, a branched or straight chain C1 to C10 alkyl group, a C3 to C7 cycloalkyl group, or an aryl group.

44. A molten polymeric composition comprising molten poly(hydroxyalkanoate) and a nucleating agent, wherein the nucleating agent comprises an ester of orotic acid, anamide 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 polymeric 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 polymeric composition of claim 44 or 45, wherein the nucleating agent is completely dissolved in the molten poly(hydroxyalkanoate).

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