Solid oral pharmaceutical compositions including co‑processed nitrosamine inhibitor and microcrystalline cellulose

Abstract

The present invention relates to a solid oral pharmaceutical composition that include: (a) an active pharmaceutical ingredient; (b) a co‑processed additive that includes a nitrosamine inhibitor and microcrystalline cellulose; and (c) optionally a pharmaceutically acceptable excipient. With the solid oral pharmaceutical compositions, at least one of: (i) the active pharmaceutical ingredient includes at least one covalently bonded amine group that is subject to conversion to nitrosamine; and / or (ii) the solid oral pharmaceutical composition includes at least one amine, that is other than the amine group covalently bonded to / within the active pharmaceutical ingredient, and which is subject to conversion to nitrosamine. The nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamine formed in the solid oral pharmaceutical composition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of the nitrosamine inhibitor.

Description

SOLID ORAL PHARMACEUTICAL COMPOSITIONS INCLUDING CO-PROCESSED NITROSAMINE INHIBITOR AND MICROCRYSTALLINE CELLULOSECROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority to United States Provisional Patent Application No. 63 / 607,783, entitled “Solid Oral Pharmaceutical Compositions Including Co- Processed Nitrosamine Inhibitor and Microcrystalline Cellulose” filed December 8, 2023, the disclosure of which is hereby incorporated by reference in its entirety.FIELD

[0002] The present invention relates to solid oral pharmaceutical compositions that include an active pharmaceutical ingredient, a co-processed additive including a nitrosamine inhibitor and microcrystalline cellulose; and optionally a pharmaceutically acceptable excipient, where the nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamine formed in the solid oral pharmaceutical composition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of the nitrosamine inhibitor.BACKGROUND

[0003] Solid oral pharmaceutical compositions can be subject to the formation of nitrosamines over time, such as during storage and / or shipment thereof. Nitrosamines are considered to be undesirable contaminants due to the potential mutagenic effects associated therewith. Nitrosamines typically form from secondary aliphatic amines, and in some instances at slower rates from tertiary aliphatic amines. Sources of nitrosamine formation include, active pharmaceutical agents that have at least one amine group covalently bonded thereto / therein that is subject to conversion to nitrosamine, and / or at least one amine present within the solid oral pharmaceutical composition, that is not covalently bonded to / within the active pharmaceutical agent, and which is subject to conversion to nitrosamine. Formation of nitrosamines also typically involves the presence of a nitrosating agent, such as, but not limited to, nitrite (NO2') and / or dinitrogen trioxide (N2O3).

[0004] It would be desirable to develop new solid oral pharmaceutical compositions that have reduced levels of nitrosamine formation. It would be further desirable that such newlydeveloped solid oral pharmaceutical compositions include additives that meet regulatory requirements, such as, but not limited to, maximum daily exposure requirements.SUMMARY

[0005] In accordance with the present invention, there is provided a solid oral pharmaceutical composition comprising: (a) an active pharmaceutical ingredient; (b) a co-processed additive comprising a nitrosamine inhibitor and microcrystalline cellulose; and (c) optionally a pharmaceutically acceptable excipient. With the solid oral pharmaceutical compositions, at least one of: (i) the active pharmaceutical ingredient comprises at least one covalently bonded amine group that is subject to conversion to nitrosamine; or (ii) the solid oral pharmaceutical composition comprises at least one amine, that is other than the amine group covalently bonded to / within the active pharmaceutical ingredient, and which is subject to conversion to nitrosamine. The nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamine formed in the solid oral pharmaceutical composition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of the nitrosamine inhibitor.

[0006] The features that characterize the present invention are pointed out with particularity in the claims, which are annexed to and form a part of this disclosure. These and other features of the invention, its operating advantages and the specific objects obtained by its use will be more fully understood from the following detailed description in which non-limiting embodiments of the invention are illustrated and described.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1 is a graphical representation of a plot of nitroso-sertraline (Nitroso-Sert) formed in a comparative solid oral pharmaceutical composition in tablet form and solid oral pharmaceutical compositions according to the present invention in tablet form as a function of time, and as described in further detail in the Examples (Part-3);

[0008] FIG. 2 is a graphical representation, in bar-graph format, of a plot of nitrososertraline (Nitroso-Sert) formed in a comparative solid oral pharmaceutical composition in tablet form and a solid oral pharmaceutical composition according to the present invention in tablet form as a function of time, during accelerated testing in HDPE bottles, and as described in further detail in the Examples (Part-4); and

[0009] FIG. 3 is a graphical representation, in bar-graph format, of a plot of nitrososertraline (Nitro-Sert) formed in a comparative solid oral pharmaceutical composition in tablet form and a solid oral pharmaceutical composition according to the present invention in tablet form as a function of time, during accelerated testing in PVC blister packaging, and as described in further detail in the Examples (Part-4).

[0010] In FIG’s 1 through 3 like characters and headings refer to the same components and / or have the same meanings, as the case may be, unless otherwise stated.DETAILED DESCRIPTION

[0011] As used herein, the articles "a," "an," and "the" include plural referents unless otherwise expressly and unequivocally limited to one referent.

[0012] Unless otherwise indicated, all ranges or ratios disclosed herein are to be understood to encompass any and all values, and subranges or subratios subsumed therein. For example, a stated range or ratio of "1 to 10" should be considered to include: any and all values therebetween, including the stated terminal values (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10); and subranges between (and inclusive of) the minimum value of 1 and the maximum value of 10, that is, all subranges or subratios beginning with a minimum value of 1 or more and ending with a maximum value of 10 or less, such as but not limited to, 1 to 6.1, 3.5 to 7.8, and 5.5 to 10.

[0013] As used herein, unless otherwise indicated, left-to-right representations of linking groups, such as divalent linking groups, are inclusive of other appropriate orientations, such as, but not limited to, right-to-left orientations. For purposes of non-limiting illustration, theOleft-to-right representation of the divalent linking groupor equivalently -C(O)O-, is inclusive of the right-to-left representation thereof,r equivalently -O(O)C- or -OC(O)-.

[0014] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as modified in all instances by the term “about.”

[0015] As used herein, “at least one of’ is synonymous with “one or more of,” whether the elements are listed conjunctively or disjunctively. For example, the phrases “at least one of A, B, and C” and “at least one of A, B, or C” each mean any one of A, B, or C, or any combination of any two or more of A, B, or C. For example, A alone; or B alone; or C alone; or A and B; or A and C; or B and C; or all of A, B, and C.

[0016] As used herein, “selected from” is synonymous with “chosen from” whether the elements are listed conjunctively or disjunctively. Further, the phrases “selected from A, B, and C” and “selected from A, B, or C” each mean any one of A, B, or C, or any combination of any two or more of A, B, or C. For example, A alone; or B alone; or C alone; or A and B; or A and C; or B and C; or all of A, B, and C.

[0017] All documents, such as but not limited to issued patents and patent applications, referred to herein, and unless otherwise indicated, are to be considered to be "incorporated by reference" in their entirety.

[0018] As used herein, the term “aliphatic group” and similar terms, such as “aliphatic substituent” means linear or branched aliphatic groups and / or cycloaliphatic groups, which are not aromatic, and which optionally include at least one carbon-carbon unsaturated linkage, such as at least one alkene linkage (-C=C-) and / or at least one alkyne linkage (-C=C-). With some embodiments, linear or branched aliphatic groups herein include 1 to 10 carbon atoms, and cycloaliphatic groups include 3 to 10 carbon atoms.

[0019] As used herein, recitations of “linear or branched” groups, such as linear or branched alkyl, are herein understood to include: a methylene group or a methyl group; groups that are linear, such as linear C2-C10 alkyl groups; and groups that are appropriately branched, such as branched C3-C10 alkyl groups.

[0020] The term “alkyl” as used herein means linear or branched, cyclic or acyclic C1-C10 alkyl. Linear or branched alkyl can include C1-C10 alkyl, such as C1-C5 alkyl, such as C2-C5 alkyl, such as C2-C4 alkyl. Examples of alkyl groups from which the various alkyl groups of the present invention can be selected from, include, but are not limited to, those recited further herein. Alkyl groups can include “cycloalkyl” groups. The term “cycloalkyl” as used herein means groups that are appropriately cyclic, such as, but not limited to, C3-C10 cycloalkyl (including, but not limited to, cyclic C3-C8 alkyl, or cyclic C5-C7 alkyl) groups.

[0021] Representative alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl,and decyl. Representative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.

[0022] As used herein, the term “nitrosamine” and similar terms such as “nitrosamines,” “nitrosamine group,” and “nitrosamine groups” are inclusive of and interchangeable with “N-nitrosamine,” “N-nitrosamines,” “N-nitrosamine group,” and “N-nitrosamine groups.”

[0023] In accordance with some embodiments of the present invention, nitrosamines, the formation of which is reduced with the present solid oral pharmaceutical compositions, are represented by the following Formula (A).Formula (A)

[0024] With reference to Formula (A), R1and R2are each independently an aliphatic group, such as a linear or branched aliphatic group, such as an alkyl group, such as a linear or branched Ci-Cio alkyl group, or a cycloaliphatic group, such as a C3-C10 cycloalkyl group. With some embodiments, R1and R2together form a cyclic group, such as a cycloaliphatic group including from 2 to 10 carbon atoms, such as 2 to 10 methylene groups (-CH2-). In accordance with some further embodiments: R1is a linear or branched C1-C10 alkyl group, or a C3-C10 cycloalkyl group; and R2is an active pharmaceutical ingredient, in which case the nitrosamine group is part of the active pharmaceutical ingredient, which with some embodiments is referred to as a N-nitrosamine active pharmaceutical ingredient. In accordance with some additional embodiments, R1and R2together form a cyclic group, such as a cycloaliphatic group, including from 2 to 10 carbon atoms, such as 2 to 10 methylene groups (-CH2-), in which the cyclic ring thereof is fused to and / or bonded (e.g., by a single bond) to at least one other ring (not shown), such as a cycloaliphatic ring and / or an aromatic ring, of the active pharmaceutical ingredient, which with some embodiments is referred to as a N-nitrosamine active pharmaceutical ingredient.

[0025] The solid oral pharmaceutical compositions of the present invention include an active pharmaceutical ingredient. With some embodiments, the active pharmaceutical ingredient includes at least one covalently bonded amine group that is subject to conversion to nitrosamine. The covalently bonded amine groups of the active pharmaceutical ingredient, with some embodiments, are each independently a secondary aliphatic amine. With somefurther embodiments, the covalently bonded amine groups of the active pharmaceutical ingredient are each independently selected from amine groups represented by the following Formulas (B) and (C).Formula (B)H- N - R3

[0026] With reference to Formula (B), R3is an aliphatic group, such as a linear or branched aliphatic group, such as an alkyl group, such as a linear or branched C1-C10 alkyl group, or a cycloaliphatic group, such as a C3-C10 cycloalkyl group. The amine group represented by Formula (B) is covalently bonded to and extends from the active pharmaceutical ingredient.Formula (C)

[0027] With reference to Formula (C), Ring A is a cycloaliphatic ring, such as a C3-C10 cycloalkyl ring, which is typically fused to and / or covalently bonded (e.g., by a single bond) to at least one other ring (not shown), such as a cycloaliphatic ring and / or an aromatic ring, of the active pharmaceutical ingredient.

[0028] The solid oral pharmaceutical composition, with some embodiments, includes at least one amine, that is other than the covalently bonded amine of the active pharmaceutical ingredient, and which is subject to conversion to nitrosamine, and which is referred to herein and with some embodiments as a free amine. The free amine of the solid oral pharmaceutical composition, with some embodiments, is present in / with the pharmaceutically acceptable excipient and / or the active pharmaceutical ingredient. The free amine, with some embodiments, is an aliphatic amine, such as a linear or branched aliphatic amine, and / or a cycloaliphatic amine. With some further embodiments, the free amine is a secondary aliphatic amine. The free amine, with some embodiments, is represented by the following Formula (D).Formula (D)

[0029] With reference to Formula (D), R4and R5are each independently an aliphatic group, such as a linear or branched aliphatic group, such as an alkyl group, such as a linear or branched C1-C10 alkyl group, or a cycloaliphatic group, such as a C3-C10 cycloalkyl group. With some embodiments, R4and R5together form a cyclic group, such as a cycloaliphatic group including from 2 to 10 carbon atoms, such as 2 to 10 methylene groups (-CH2-).

[0030] The active pharmaceutical ingredient, of the solid oral pharmaceutical compositions of the present invention, includes synthetic and / or natural active pharmaceutical ingredients, and / or pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts of the active pharmaceutical ingredient, include but are not limited to HC1 salts thereof. General classes of active pharmaceutical ingredients include, but are not limited to: analgesics; hypertension drugs, such as angiotensin II receptor blockers (ARBs), such as sartans, such as azilsartan, candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, and eprosartan; further hypertension drugs, such as beta blockers, such as propranolol, sotalol, acebutalol, metoprolol, atenolol, and labetolol; histamine H2-receptor antagonists (or histamine-2 blockers), such a cimetidine, ranitidine, nizatidine, and famotidine; antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), such sertraline, citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, and vortioxetine.

[0031] With some embodiments, the active pharmaceutical ingredient includes at least one of an angiotensin II receptor blocker, a beta blocker, a histamine H2-receptor antagonist, a selective serotonin reuptake inhibitor, and / or pharmaceutically acceptable salts of each thereof.

[0032] The active pharmaceutical ingredient, with some embodiments of the present invention, includes at least one covalently bonded amine group that is subject to conversion to nitro s amine.

[0033] In accordance with some further embodiments, the active pharmaceutical ingredient includes at least one of sertraline, a pharmaceutically acceptable salt of sertraline, propranolol, or a pharmaceutically acceptable salt of propranolol.

[0034] Sertraline can be represented by the following Formula (la),Formula (la)

[0035] A chemical name for sertraline, as represented by Formula (la), is (lS,4S)-4-(3,4- dichlorophenyl)-N-methyl-l,2,3,4-tetrahydronaphthalen-l-amine.

[0036] The following Formula (lb) is a representative structure for N-nitroso sertraline (also referred to herein as nitroso-sertraline),Formula (lb)

[0037] A chemical name for the N-nitroso sertraline, as represented by Formula (lb), is N- ((lS,4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydronaphthalen-l-yl)-N-methylnitrous amide.

[0038] Propranolol can be represented by the following Formula (Ila),Formula (Ila)

[0039] A chemical name for propranolol, as represented by Formula (Ila), is 1- (isopropylamino)-3-(naphthalen-l-yloxy)propan-2-ol.

[0040] The following Formula (lib) is a representative structure for N-nitroso propranolol (also referred to herein as nitroso-propranolol),Formula (lib)

[0041] A chemical name for the N-nitroso propranolol, as represented by Formula (lib), is N-(2-hydroxy-3-(naphthalen-l-yloxy)propyl)-N-isopropylnitrous amide.

[0042] The active pharmaceutical ingredient is present in the solid oral pharmaceutical composition, in any suitable amount, such as a pharmaceutically effective amount. With some embodiments, the active pharmaceutical ingredient is present in the solid oral pharmaceutical composition in an amount of from 10 to 60 percent by weight, or from 20 to 50 percent by weight, or from 30 to 40 percent by weight, the percent weights in each case being based on the total weight of the solid oral pharmaceutical composition.

[0043] The solid oral pharmaceutical compositions of the present invention include a co-processed additive comprising a nitrosamine inhibitor and microcrystalline cellulose. As used herein, the term “a co-processed additive comprising a nitrosamine inhibitor and microcrystalline cellulose” means that at least the nitrosamine inhibitor and microcrystalline cellulose, of the additive, are processed together (or co-processed) separate from (such as prior to) being combined with the active pharmaceutical ingredient and the optional pharmaceutically acceptable excipient. Preparation of the co-processed additive, with some embodiments involves, first mixing the nitrosamine inhibitor with an appropriate solvent, such as an alcohol, such as ethanol, to form a nitrosamine inhibitor solution. The next (or second) step involves combining (or mixing) together the nitrosamine inhibitor solution with microcrystalline cellulose, such as by spraying the nitrosamine inhibitor solution into a high shear granulator containing the microcrystalline cellulose. Within the high shear granulator,the nitrosamine inhibitor solution and the microcrystalline cellulose are allowed to mix together for an appropriate amount of time, such as 5 to 10 minutes, which results in the formation of an intermediate co-processed additive that includes solvent, nitrosamine inhibitor, and microcrystalline cellulose. The next (or third) step involves drying the intermediate co-processed additive by exposure to elevated temperature, such as a temperature of greater than 25°C, such as 40°C, for a period of time, such as at least one hour, such as 4 hours, which results in the formation of a co-processed additive including the nitrosamine inhibitor and microcrystalline cellulose, which may be agglomerated with some embodiments. Optionally, and if required, the agglomerated co-processed additive is subjected to de-agglomeration, such as by screening, which results in the formation of a co-processed additive according to the present invention, which comprises the nitrosamine inhibitor and microcrystalline cellulose, and which is (has been) de-agglomerated.

[0044] In accordance with some embodiments of the present invention, the co-processed additive consists essentially of a nitrosamine inhibitor and microcrystalline cellulose. In accordance with some further embodiments of the present invention, the co-processed additive consists of a nitrosamine inhibitor and microcrystalline cellulose.

[0045] The nitrosamine inhibitor, with some embodiments, is present in the co-processed additive including a nitrosamine inhibitor and microcrystalline cellulose, in an amount of from 0.1 wt. % to 10.0 wt. %, or from 0.1 wt. % to 5.0 wt. %, or from 0.1 wt.% to 2.5 wt.%, or from 0.3 wt.% to 2.0 wt.%, or from 0.5 wt.% to 1.5 wt.%, or from 0.75 wt.% to 1.25 wt.%, or from 0.8 wt.% to 1.1 wt.%, the weight percents in each case being based on the total weight of the co-processed additive including a nitrosamine inhibitor and microcrystalline cellulose. The microcrystalline cellulose, with some embodiments, is present in the co-processed additive including a nitrosamine inhibitor and microcrystalline cellulose, in an amount of from 90.0 wt. % to 99.9 wt. %, or from 95.0 wt. % to 99.9 wt. %, or from 97.5 wt.% to 99.9 wt.%, or from 98 wt.% to 99.7 wt.%, or from 98.5 wt.% to 99.5 wt.%, or from 98.75 wt.% to 99.25 wt.%, or from 98.9 wt.% to 99.2 wt.%, the weight percents in each case being based on the total weight of the co-processed additive including a nitrosamine inhibitor and microcrystalline cellulose.

[0046] In accordance with some embodiments of the present invention, the microcrystalline cellulose is in the form of an inert, light colored (such as white), free-flowing powder having: a D50 particle size of from 50 micrometers to 200 micrometers (such as from 80 micrometers to 150 micrometers); a moisture content of 2.0 to 5.0 percent by weight, based on total weight; and a bulk density of 0.2 g / cc to 0.5 g / cc (such as 0.25 g / cc to 0.35 g / cc). In accordance withsome embodiments, the microcrystalline cellulose is obtained commercially, such as AVICEL PH 102 microcrystalline cellulose, which is commercially available from DuPont.

[0047] The nitrosamine inhibitor, of the solid oral pharmaceutical compositions of the present invention, includes, with some embodiments, at least one of alkyl3.4.5-trihydroxybenzoate (such as linear or branched C2-C5 alkyl 3,4,5-trihydroxybenzoate), butylated hydroxyanisol, butylated hydroxy toluene, glycine, histidine, lysine, ascorbic acid, or alkali metal ascorbate. The alkali metal (or alkali metal cation) of the alkali metal ascorbate, with some embodiments, is selected from lithium cation, sodium cation, and / or potassium cation.

[0048] In accordance with some further embodiments, the nitrosamine inhibitor includes at least one of n-propyl 3,4,5-trihydroxybenzoate, butylated hydroxyanisol, butylated hydroxytoluene, glycine, histidine, lysine, ascorbic acid, or sodium ascorbate.

[0049] The nitrosamine inhibitor, in accordance with some embodiments of the solid oral pharmaceutical compositions of the present invention, includes at last one alkyl3.4.5-trihydroxybenzoate, such as a linear or branched C1-C10 alkyl 3,4,5-trihydroxybenzoate, or a linear or branched C2-C5 alkyl 3,4,5-trihydroxybenzoate. With some embodiments, the alkyl 3,4,5-trihydroxybenzoate can be represented by the following Formula (III),Formula (III)

[0050] With reference to Formula (III), R6is a linear or branched C1-C10 alkyl group, such as a linear or branched C2-C5 alkyl group. With some embodiments of the present invention, R6of Formula (III), is an n-propyl or iso-propyl group.

[0051] The alkyl 3,4,5-trihydroxybenzoate can also be referred to as an alkyl gallate, such as a linear or branched C1-C10 alkyl gallate, or a linear or branched C2-C5 alkyl gallate.

[0052] With some embodiments of the present invention, the nitrosamine inhibitor includes n-propyl 3,4,5-trihydroxybenzoate (or n-propyl gallate, which is also referred to herein as propyl gallate).

[0053] In accordance with the present invention, the nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamine formed in the solid oral pharmaceutical composition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of the nitrosamine inhibitor.

[0054] As used herein, the recitation of “a comparative solid oral pharmaceutical composition that is free of the nitrosamine inhibitor” means a comparative composition that includes the same active pharmaceutical ingredient, the same co-processed additive comprising a nitrosamine inhibitor and microcrystalline cellulose, and the same optional pharmaceutically acceptable excipient (if present), in the same relative amounts, does not include the nitrosamine inhibitor, and which is prepared and evaluated under the same conditions, as the solid oral pharmaceutical composition according to the present invention.

[0055] The amount of nitrosamine formed in the inventive and comparative solid oral pharmaceutical compositions can be determined in accordance with art-recognized analytical methods. With some embodiments, the amount of nitrosamine formed in the inventive and comparative solid oral pharmaceutical compositions is determined using liquid chromatography-mass spectrometry (LC-MS).

[0056] In accordance with some embodiments, shortly after preparation of the inventive and comparative solid oral pharmaceutical compositions, an initial (or to) amount (or level) of nitrosamine is determined. The inventive and comparative solid oral pharmaceutical compositions are then typically subjected to accelerated testing under controlled conditions of elevated temperature, such as 50°C or 70°C, and relative humidity (RH), such as 70% RH or 75% RH. Test samples are typically withdrawn and analyzed to determine the amount of nitrosamine formed, over a period of time, such as days (e.g., 3, 6, and / or 30 days).

[0057] In accordance with some embodiments, the reduction in the amount of nitrosamine formed in the inventive solid oral pharmaceutical compositions, over a period of time, is characterized as a percent reduction relative to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition, which is calculated using the following Equation-(l):Equation-(l)(comparative amount of nitrosamine formed at - (inventive amount of nitrosamine formed at100 x -(comparative amount of nitrosamine formed at

[0058] With reference to Equation-(l), the “comparative amount of nitrosamine formed at tx” means the amount of nitrosamine formed in the comparative solid oral pharmaceutical composition at time tx. With further reference to Equation-(l), the “inventive amount of nitrosamine formed at tx” means the amount of nitrosamine formed in the solid oral pharmaceutical composition according to the present invention at time tx.

[0059] With some embodiments of the present invention, the amount of nitrosamine formed in the solid oral pharmaceutical composition according to the present invention is reduced by at least 10 percent by weight, or at least 20 percent by weight, or at least 30 percent by weight, or at least 40 percent by weight, or at least 50 percent by weight, in each case as compared to the amount of nitrosamine formed in the comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor, in each case under the same test and environmental conditions, and for the same period of time.

[0060] With some further embodiments of the present invention, the amount of nitrosamine formed in the solid oral pharmaceutical composition according to the present invention is reduced by at least 75 percent by weight, compared to the amount of nitrosamine formed in the comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor, in each case under the same test and environmental conditions, and for the same period of time.

[0061] With some further embodiments of the present invention, the amount of nitrosamine formed in the solid oral pharmaceutical composition according to the present invention is reduced by at least 80 percent by weight, or at least 85 percent by weight, or at least 90 percent by weight, or at least 95 percent by weight, in each case as compared to the amount of nitrosamine formed in the comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor, in each case under the same test and environmental conditions, and for the same period of time.

[0062] With some further embodiments of the present invention, the amount of nitrosamine formed in the solid oral pharmaceutical composition according to the present invention is reduced by from 92 percent by weight to less than or equal to 100 percent by weight, or by 93 percent by weight to less than or equal to 98 percent by weight, compared to the amount ofnitrosamine formed in the comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor, in each case under the same test and environmental conditions, and for the same period of time.

[0063] The nitrosamine inhibitor can be present in the solid oral pharmaceutical composition according to the present invention in any amount, provided such amount is at least sufficient so as to reduce the amount of nitrosamine formed in the solid oral pharmaceutical composition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

[0064] With some embodiments, the nitrosamine inhibitor is present in an amount of at least 0.05 percent by weight, based on weight of the active pharmaceutical ingredient.

[0065] With some further embodiments, the nitrosamine inhibitor is present in an amount of from 0.05 percent by weight to 4 percent by weight, or from 0.05 percent by weight to 3 percent by weight, or from 0.05 percent by weight to 2.5 percent by weight, based on weight of the active pharmaceutical ingredient, inclusive of the recited amounts.

[0066] With some additional embodiments of the present invention, the nitrosamine inhibitor is present in an amount of from 0.5 percent by weight to 3 percent by weight, or from 0.5 percent by weight, to 2.5 percent by weight, based on weight of the active pharmaceutical ingredient, inclusive of the recited amounts.

[0067] The active pharmaceutical additive, the co-processed additive including a nitrosamine inhibitor and microcrystalline cellulose; and the optional pharmaceutically acceptable excipient are combined together in accordance with art-recognized methods, such as, but not limited to, dry mixing methods.

[0068] The solid oral pharmaceutical compositions of the present invention optionally include at least one pharmaceutically acceptable excipient. Classes of pharmaceutically acceptable excipients include, but are not limited to: diluents, such as sugar compounds, such as lactose, dextrin, glucose, sucrose, and sorbitol, and / or inorganic compounds, such as silicates, calcium salts, magnesium salts, sodium chloride, and potassium chloride; binders, compression aids, and granulating agents, such as natural and / or synthetic polymers, such as starches, polymeric sugars, sugar alcohol, and cellulose derivatives; disintegrants, such as starch, cellulose derivatives, alginates, and crospovidone (cross-linked polyvinylpyrrolidone); glidants, such as anhydrous silicon and other silica compounds; and lubricants, such as stearic acid and salts of stearic acid.

[0069] With some embodiments, the optional pharmaceutically acceptable excipient includes at least one of microcrystalline cellulose, sucrose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium starch glycolate, starch, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, magnesium stearate, oleic acid, stearic acid, stearyl alcohol, calcium carbonate, dextrose, lactose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, silica, titanium dioxide, gelatin, or triglycerides. With some further embodiments, the optional pharmaceutically acceptable excipient is free of (does not include) microcrystalline cellulose.

[0070] The optional pharmaceutically acceptable excipient(s) can be present in the solid oral pharmaceutical compositions of the present invention in any suitable amount. With some embodiments, the optional pharmaceutically acceptable excipient is present in an amount of from 0.05 to 99.5 percent by weight, or from 5 to 95 percent by weight, or from 10 to 90 percent by weight, the percent weights in each case being based on the total weight of the solid oral pharmaceutical composition. These recited amounts and ranges of the optional pharmaceutically acceptable excipient do not include the amount of microcrystalline cellulose present in the co-processed additive comprising a nitrosamine inhibitor and microcrystalline cellulose.

[0071] The solid oral pharmaceutical compositions of the present invention can be in any suitable form. With some embodiments, the solid oral pharmaceutical composition of the present invention is in a form selected from tablets, capsules, and free flowing granules. The solid oral pharmaceutical compositions of the present invention can be formed into tablets, capsules, and / or free flowing granules in accordance with art-recognized methods.

[0072] The present invention can be further characterized by one or more of the following non-limiting clauses.

[0073] Clause 1: A solid oral pharmaceutical composition comprising:(a) an active pharmaceutical ingredient;(b) a co-processed additive comprising a nitrosamine inhibitor and microcrystalline cellulose; and(c) optionally a pharmaceutically acceptable excipient, wherein at least one of, (i) said active pharmaceutical ingredient comprises at least one covalently bonded amine group that is subject to conversion to nitrosamine; or (ii) said solidoral pharmaceutical composition comprises at least one amine that is subject to conversion to nitrosamine, and wherein said nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamine formed in said solid oral pharmaceutical composition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

[0074] Clause 2: The solid oral pharmaceutical composition of clause 1, wherein said active pharmaceutical ingredient comprises at least one of, an angiotensin II receptor blocker, a beta-blocker, a histamine H2-receptor antagonist, a selective serotonin reuptake inhibitor, or pharmaceutically acceptable salts of one or more thereof.

[0075] Clause 3: The solid oral pharmaceutical composition of clause 1 or clause 2, wherein said active pharmaceutical ingredient comprises at least one covalently bonded amine group that is subject to conversion to nitrosamine.

[0076] Clause 4: The solid oral pharmaceutical composition of any one of clauses 1 to 3, wherein said active pharmaceutical ingredient comprises at least one of sertraline, a pharmaceutically acceptable salt of sertraline, propranolol, or a pharmaceutically acceptable salt of propranolol.

[0077] Clause 5: The solid oral pharmaceutical composition of any one of clauses 1 to 4, wherein said nitrosamine inhibitor comprises at least one of linear or branched C2-C5 alkyl 3,4,5-trihydroxybenzoate, butylated hydroxyanisol, butylated hydroxytoluene, glycine, histidine, lysine, ascorbic acid, or alkali metal ascorbate.

[0078] Clause 6: The solid oral pharmaceutical composition of any one of clauses 1 to 5, wherein said nitrosamine inhibitor comprises at least one of n-propyl 3,4,5-trihydroxybenzoate, butylated hydroxyanisol, butylated hydroxy toluene, glycine, histidine, lysine, ascorbic acid, or sodium ascorbate.

[0079] Clause 7: The solid oral pharmaceutical composition of any one of clauses 1 to 6, wherein said amount of said nitrosamine inhibitor is at least 0.05 percent by weight, based on weight of said active pharmaceutical ingredient.

[0080] Clause 8: The solid oral pharmaceutical composition of any one of clauses 1 to 7, wherein said amount of said nitrosamine inhibitor is from 0.05 percent by weight to 4 percent by weight, based on weight of said active pharmaceutical ingredient.

[0081] Clause 9: The solid oral pharmaceutical composition of any one of clauses 1 to 8, wherein, said amount of said nitrosamine inhibitor is from 0.5 percent by weight to 3 percent by weight, based on weight of said active pharmaceutical ingredient.

[0082] Clause 10: The solid oral pharmaceutical composition of any one of clauses 1 to 9, wherein the amount of nitrosamine formed in said solid oral pharmaceutical composition is reduced by at least 50 percent by weight, compared to the amount of nitrosamine formed in said comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

[0083] Clause 11: The solid oral pharmaceutical composition of any one of clauses 1 to 10, wherein the amount of nitrosamine formed in said solid oral pharmaceutical composition is reduced by at least 75 percent by weight, compared to the amount of nitrosamine formed in said comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

[0084] Clause 12: The solid oral pharmaceutical composition of any one of clauses 1 to 11, wherein the amount of nitrosamine formed in said solid oral pharmaceutical composition is reduced by at least 80 percent by weight, compared to the amount of nitrosamine formed in said comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

[0085] Clause 13: The solid oral pharmaceutical composition of any one of clauses 1 to 12, wherein the pharmaceutically acceptable excipient comprises at least one of a diluent, a binder, a compression aid, a granulating agent, a disintegrant, a glidant, or a lubricant.

[0086] Clause 14: The solid oral pharmaceutical composition of any one of clauses 1 to 13, wherein said pharmaceutically acceptable excipient comprises at least one of microcrystalline cellulose, sucrose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium starch glycolate, starch, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, magnesium stearate, oleic acid, stearic acid, stearyl alcohol, calcium carbonate, dextrose, lactose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, silica, titanium dioxide, gelatin, or triglycerides.

[0087] Clause 15: The solid oral pharmaceutical composition of any one of clauses 1 to 14, wherein said solid oral pharmaceutical composition is in a form selected from tablets, capsules, and free flowing granules.

[0088] The present invention is more particularly described in the following examples, which are intended to be illustrative only, since numerous modifications and variations therein will be apparent to those skilled in the art. Unless otherwise specified, all parts and all percentages are by weight.EXAMPLES

[0089] In Part 1 of the following examples, there is described the preparation and evaluation of granular comparative solid oral pharmaceutical compositions and those according to the present invention, which include sertraline HC1 as the active pharmaceutical ingredient (API), and nitrosamine inhibitors as indicated. In Part 2 there is described the preparation and evaluation of granular comparative solid oral pharmaceutical compositions and those according to the present invention, which include propranolol HC1 as the active pharmaceutical ingredient, and nitrosamine inhibitors as indicated. In Part 3 there is described comparative solid oral pharmaceutical compositions and those according to the present invention, in tablet form, which include sertraline HC1 as the API, and different levels of propyl gallate (n-propyl 3,4,5-trihydroxybenzoate) as the nitrosamine inhibitor. In Part 4 there is described the preparation comparative solid oral pharmaceutical compositions and those according to the present invention, in tablet form, which include sertraline HC1 as the API, and propyl gallate as the nitrosamine inhibitor, and evaluation thereof in bottle and blister package testing. In Part 5 there is described the preparation and evaluation of comparative solid oral pharmaceutical compositions and those according to the present invention, in tablet form, which include propranolol HC1 as the API, and propyl gallate (PG) or ascorbic acid (AA) as the nitrosamine inhibitor.Part-1

[0090] Solid oral pharmaceutical compositions, in granular form, according to the present invention (Ex’s 1-5) were prepared by dissolving the nitrosamine inhibitor (as indicated in Table 1) in ethanol with mixing for 30 minutes to form a nitrosoamine inhibitor solution, which was then combined with microcrystalline cellulose (AVICEL PH 102 obtained commercially from DuPont) (MCC) by spraying the nitrosamine inhibitor solution into a high shear granulator containing the microcrystalline cellulose (for 5 minutes), to form an intermediate co-processed additive that included solvent, nitrosamine inhibitor, and microcrystalline cellulose. The intermediate co-processed additive was next dried in an oven at 40°C for 4 hours, which resulted in the formation of an agglomerated co-processed additive, which was de-agglomerated by screening, which resulted in the formation of a co-processed additiveincluding nitrosamine inhibitor and MCC, according to the present invention. The co-processed additive including nitrosamine inhibitor and MCC was combined by dry-mixing with sertraline HC1 (the active pharmaceutical ingredient / API). The control (CE- 1), including only sertraline HC1 and MCC was prepare by dry-mixing sertraline HC1 and MCC together.

[0091] The weight ratios of API : MCC : nitrosamine inhibitor for CE-1 and Ex’s 1-5 are provided in Table 1.

[0092] The control and inventive solid oral pharmaceutical compositions were evaluated by liquid chromatography - mass spectrometry (LC-MS) initially to determine initial (to) amounts of nitroso-sertraline. The comparative and inventive test samples were then subjected to 70°C at ambient % RH (relative humidity), with samples being withdrawn and evaluated at 3 and 6 days to determine the amount of nitroso-sertraline formed by LC-MS analysis. The results are tabulated in the following Table 1.TABLE 1(1)BHA is butylated hydroxyanisol.(2)BHT is butylated hydroxytolulene.(3)PG is propyl gallate.(4)The API (active pharmaceutical ingredient) in each case was sertraline HC1.(5)MCC is microcrystalline cellulose(6)N-Inhib means nitrosamine inhibitor.(7)Nitroso-Sert means nitroso-sertraline.

[0093] With reference to Table 1, for day 3, the solid oral pharmaceutical compositions of inventive Ex’s 1-5 each were determined to have a percent (by weight) reduction in the formation of nitroso-sertraline, relative to the amount / weight of nitrosamine formed in comparative CE-1 of: 59.6 %; 53.8 %; 53.8 %; 57.7 %; and 44.2 %, respectively. With further reference to Table 1, for day 6, the solid oral pharmaceutical compositions of inventive Ex’s 1-5 each were determined to have a percent (by weight) reduction in the formation of nitroso-sertraline, relative to the amount / weight of nitrosamine formed in CE-1 of: 54.1 %; 34.4 %; 62.3 %; 47.5 %; and 36.1 %.Part-2

[0094] The co-processed additive including nitrosamine inhibitor(s) (as indicated in Table 2) and microcrystalline cellulose (of Ex’s 6-15) were prepared, and then combined with propranolol HC1, in accordance with the description provided in Part-1. The control (CE-2), including only propranolol HC1 and MCC was prepared by dry-mixing the propranolol HC1 and MCC together. The weight ratios of API : MCC : nitrosamine inhibitor for CE-2 and Ex’s 6-15 are provided in Table 2.

[0095] The control and inventive solid oral pharmaceutical compositions were evaluated by liquid chromatography - mass spectrometry (LC-MS) initially to determine initial (to) amounts of nitroso-propranolol. The comparative and inventive test samples were then subjected to 70°C at ambient % RH (relative humidity), with samples being withdrawn and evaluated at 3 and 6 days to determine the amount of nitroso-propranolol formed by LC-MS analysis. The results are tabulated in the following Table 2.TABLE 2(8)The API in each case was propranolol HC1.(9)Nitroso-PP means nitroso-propranolol HC1.

[0096] With reference to Table 2, for day 3, the solid oral pharmaceutical compositions of inventive Ex’s 6-15 each were determined to have a percent (by weight) reduction in the formation of nitroso-propranolol, relative to the amount / weight of nitrosamine formed in comparative CE-2 of: 22.6 %; + 17.0%; 58.5 %; 75.5 %; 13.2 %; 84.9 %; 83.0 %; 73.6 %; 22.6 %; and 39.6 %, respectively. With further reference to Table 2, for day 6, the solid oral pharmaceutical compositions of inventive Ex’s 6-15 each were determined to have a percent (by weight) reduction in the formation of nitroso-propranolol, relative to the amount / weight of nitrosamine formed in CE-2 of: 58.8 %; 52.9 %; 50.0 %; 88.2 %; 69.6 %; 91.17 %; 89.2 %; 90.2 %; 80.4 %; and 84.3 %, respectively.Part-3

[0097] Co-processed additive including propyl gallate (PG) and microcrystalline cellulose (MCC) was prepared in accordance with the description provided in Part-1. Sertraline HC1 was granulated with hydroxypropyl cellulose (HPC) and water, following by drying of the resulting granules in a fluid bed dryer, and then milling of the dried granules. The milled granules including sertraline HC1 and HPC were dry-blended with the co-processed additive (including PG and MCC), MCC, dicalcium phosphate, sodium starch glycolate, and magnesium stearate, followed by compressing to form tablets, which were coated with a nonfunctional material. The co-processed additive was included in the dry-blends in amounts sufficient to provide percent weights of propyl gallate (PG) as indicated in the following Table 3, in each case based on weight of the sertraline HC1. The control (CE-3), including only sertraline HC1 and MCC was prepared and formed into tablets in accordance with the preceding description.

[0098] The control (CE-3) and inventive (Ex’s 16-19) solid oral pharmaceutical compositions, in tablet form, were evaluated by liquid chromatography - mass spectrometry (LC-MS) initially to determine initial (to) amounts of nitroso-sertraline. The comparative and inventive test samples, in tablet form, were then subjected to 70°C at ambient % RH (relative humidity), with samples being withdrawn and evaluated at 3 and 6 days to determine the amount of nitroso-sertraline formed by LC-MS analysis. The results are tabulated in the following Table 3.TABLE 3(W) percent by weight of propyl gallate (PG) based on weight of sertraline HC1.

[0099] The results of Table 3 are presented graphically in FIG. 1 of the drawings as nitroso-sertraline (ppm) plotted as a function of time (0, 3, and 6 days) for each of CE-3 (indicated as No PG), and Ex’s 16-19 (indicated as 0.1% PG, 0.5% PG, 1% PG, and 2% PG). With reference to Table 3, for day 3, the solid oral pharmaceutical compositions, in tablet form, of inventive Ex’s 16-19 each were determined to have a percent (by weight) reduction in the formation of nitroso-sertraline, relative to the amount / weight of nitrosamine formed in comparative CE-3 of: 39.5 %; 71.6 %; 84.1 %; and 95.8 %, respectively. With further reference to Table 3, for day 6, the solid oral pharmaceutical compositions, in tablet form, of inventive Ex’s 16-19 each were determined to have a percent (by weight) reduction in the formation of nitroso-sertraline, relative to the amount / weight of nitrosamine formed in CE-3 of: 25.6 %; 78.8 %; 82.7 %; and 95.4 %, respectively.Part-4

[0100] Control (CE-4 and CE-5) and inventive (Ex’s 20 and 21) solid oral pharmaceutical compositions, in tablet form, were prepared as described in Part-3, with the inventive tablets containing 1 wt.% of propyl gallate (PG) based on weight of sertraline HC1.

[0101] Control tablets (CE-4; No PG) and inventive tablets (Ex 20; 1% PG) were placed in separate HDPE bottles and subjected to 40°C and 75 % relative humidity (RH) for a period of 6 months, with samples being withdrawn at 0 (initially), 0.5, 1, 2, 3, and 6 months to determine the amount of nitroso-sertraline formed, by and liquid chromatography - mass spectrometry (LC-MS) analysis, the results of which are tabulated in the following Table 4, and presented graphically as a bar graph in FIG. 2 of the drawings.TABLE 4HDPE Bottle Evaluation

[0102] Control tablets (CE-5; No PG) and inventive tablets (Ex 21; 1% PG) were placed in separate PVC blister packs and subjected to 40°C and 75 % relative humidity (RH) for a period of 6 months, with samples being withdrawn at 0 (initially), 0.5, 1, 2, 3, and 6 months to determine the amount of nitroso-sertraline formed, by and liquid chromatography - mass spectrometry (LC-MS) analysis, the results of which are tabulated in the following Table 5, and presented graphically as a bar graph in FIG. 3 of the drawings.TABLE 5PVC Blister Package EvaluationPart-5

[0103] Control (CE-6) and inventive (Ex’s 22 and 23) solid oral pharmaceutical compositions, in tablet form, containing propranolol HC1 as the API, were prepared as described in Part-3, with the inventive tablets containing 1 wt.% of propyl gallate (PG) (Ex- 22) or 1 wt.% of ascorbic acid (Ex-23) based, in each case, on weight of propranolol HC1. The control (CE-6) and inventive (Ex’s 22 and 23) solid oral pharmaceutical compositions, in tablet form, were evaluated by liquid chromatography - mass spectrometry (LC-MS) initially to determine initial (to) amounts of nitroso-sertraline. A first set of control (CE-6) and inventive (Ex’s 22 and 23) tablets were subjected to 70°C at ambient % RH, with samples being withdrawn at 3 and 6 days, and evaluated for the amount of nitroso-propranolol HCL formed (as determined by LC-MS). A second set of control (CE-6) and inventive (Ex’s 22 and 23) tablets were subjected to 50°C at ambient % RH, with samples being withdrawn at 2 and 4 weeks, and evaluated for the amount of nitroso-propranolol HCL formed (as determined by LC-MS). The results are summarized in the following Tables 6 and 7.TABLE 670°C at Ambient %RH(9)Nitroso-PP means nitroso-propranolol HC1.(11)Percent by weight of propyl gallate based on weight of propranolol HC1.(!2) percen( by weight of ascorbic acid based on weigh to propranolol HC1.TABLE 750°C at Ambient %RH

[0104] With reference to Table 6, for day 3, the solid oral pharmaceutical compositions, in tablet form, of inventive Ex’s 22 and 23 each were determined to have a percent (by weight) reduction in the formation of nitroso-propranolol HC1, relative to the amount / weight of nitrosamine formed in comparative CE-6 of: 84.2 %; and 81.1 %, respectively. With further reference to Table 6, for day 6, the solid oral pharmaceutical compositions, in tablet form, of inventive Ex’s 22 and 23 each were determined to have a percent (by weight) reduction in the formation of nitroso-propranolol HC1, relative to the amount / weight of nitrosamine formed in comparative CE-6 of: 78.7 %; and 83.4 %, respectively.

[0105] With reference to Table 7, at 2 weeks, the solid oral pharmaceutical compositions, in tablet form, of inventive Ex’s 22 and 23 each were determined to have a percent (by weight) reduction in the formation of nitroso-propranolol HC1, relative to the amount / weight of nitrosamine formed in comparative CE-6 of: 25.5 %; and 35.4 %, respectively. With further reference to Table 7, at 4 weeks, the solid oral pharmaceutical compositions, in tablet form, of inventive Ex’s 22 and 23 each were determined to have a percent (by weight) reduction in the formation of nitroso-propranolol HC1, relative to the amount / weight of nitrosamine formed in comparative CE-6 of: 66.1 %; and 71.4 %, respectively.

[0106] The results summarized in the above Examples demonstrate that solid oral pharmaceutical compositions according to the present invention provide a significant reduction in the amount of nitrosamine formed relative to comparative solid oral pharmaceutical compositions that do not include a nitrosamine inhibitor.

[0107] The present invention has been described with reference to specific details of particular embodiments thereof. It is not intended that such details be regarded as limitations upon the scope of the invention except insofar as to the extent that they are included in the accompanying claims.

Claims

WHAT IS CLAIMED IS:

1. A solid oral pharmaceutical composition comprising:(a) an active pharmaceutical ingredient;(b) a co-processed additive comprising a nitrosamine inhibitor and microcrystalline wax; and(c) optionally a pharmaceutically acceptable excipient, wherein at least one of, (i) said active pharmaceutical ingredient comprises at least one covalently bonded amine group that is subject to conversion to nitrosamine; or (ii) said solid oral pharmaceutical composition comprises at least one amine that is subject to conversion to nitrosamine, and wherein said nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamine formed in said solid oral pharmaceutical composition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

2. The solid oral pharmaceutical composition of claim 1, wherein said active pharmaceutical ingredient comprises at least one of, an angiotensin II receptor blocker, a beta-blocker, a histamine H2-receptor antagonist, a selective serotonin reuptake inhibitor, or pharmaceutically acceptable salts of one or more thereof.

3. The solid oral pharmaceutical composition of claim 1, wherein said active pharmaceutical ingredient comprises at least one covalently bonded amine group that is subject to conversion to nitrosamine.

4. The solid oral pharmaceutical composition of claim 3, wherein said active pharmaceutical ingredient comprises at least one of sertraline, a pharmaceutically acceptable salt of sertraline, propranolol, or a pharmaceutically acceptable salt of propranolol.

5. The solid oral pharmaceutical composition of claim 1, wherein said nitrosamine inhibitor comprises at least one of linear or branched C2-C5 alkyl 3,4,5-trihydroxybenzoate, butylated hydroxyanisol, butylated hydroxytoluene, glycine, histidine, lysine, ascorbic acid, or alkali metal ascorbate.

6. The solid oral pharmaceutical composition of claim 5, wherein said nitrosamine inhibitor comprises at least one of n-propyl 3,4,5-trihydroxybenzoate, butylated hydroxyanisol, butylated hydroxytoluene, glycine, histidine, lysine, ascorbic acid, or sodium ascorbate.

7. The solid oral pharmaceutical composition of claim 1, wherein said amount of said nitrosamine inhibitor is at least 0.05 percent by weight, based on weight of said active pharmaceutical ingredient.

8. The solid oral pharmaceutical composition of claim 7, wherein said amount of said nitrosamine inhibitor is from 0.05 percent by weight to 4 percent by weight, based on weight of said active pharmaceutical ingredient.

9. The solid oral pharmaceutical composition of claim 8, wherein, said amount of said nitrosamine inhibitor is from 0.5 percent by weight to 3 percent by weight, based on weight of said active pharmaceutical ingredient.

10. The solid oral pharmaceutical composition of claim 1, wherein the amount of nitrosamine formed in said solid oral pharmaceutical composition is reduced by at least 50 percent by weight, compared to the amount of nitrosamine formed in said comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

11. The solid oral pharmaceutical composition of claim 1, wherein the amount of nitrosamine formed in said solid oral pharmaceutical composition is reduced by at least 75 percent by weight, compared to the amount of nitrosamine formed in said comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

12. The solid oral pharmaceutical composition of claim 1, wherein the amount of nitrosamine formed in said solid oral pharmaceutical composition is reduced by at least 80 percent by weight, compared to the amount of nitrosamine formed in said comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

13. The solid oral pharmaceutical composition of claim 1, wherein said pharmaceutically acceptable excipient comprises at least one of sucrose, hydroxypropylcellulose, hydroxypropyl methylcellulose, sodium starch glycolate, starch, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, magnesium stearate, oleic acid, stearic acid, stearyl alcohol, calcium carbonate, dextrose, lactose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, silica, titanium dioxide, gelatin, or triglycerides.

14. The solid oral pharmaceutical composition of claim 1 , wherein said solid oral pharmaceutical composition is in a form selected from tablets, capsules, and free flowing granules.

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