WO2023139294A1

WO2023139294A1 - Stable composition of chloral hydrate

Info

Publication number: WO2023139294A1
Application number: PCT/EP2023/053066
Authority: WO
Inventors: James Mcquillan
Original assignee: Atnahs Pharma Uk Limited
Priority date: 2022-07-18
Filing date: 2023-02-08
Publication date: 2023-07-27
Also published as: GB2614972B; GB2617419A; GB202210518D0; GB2617419B; GB2614972A

Abstract

The present invention provides an oral chloral hydrate solution that is stable over a period of at least 12 months, such that the solution contains not more than 300 ppm of chloroform, not more than 800 ppm of formic acid and not more than 100 ppm of monochloroacetaldehyde. The invention also provides means of preparing the stable chloral hydrate solution.

Description

STABLE COMPOSITION OF CHLORAL HYDRATE

This application claims the benefit of the UK patent application GB 2210518.3 filed 18 July 2022, which is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a stable composition of chloral hydrate and particularly, although not exclusively, to its use as an oral solution in the short-term treatment of severe insomnia and for sedation in pediatric patients. The composition is stable over its shelflife and has low levels of chloroform and other impurities at the end of shelf life.

BACKGROUND OF THE INVENTION

Chloral Hydrate Oral Solution is indicated in adults for the short-term treatment (maximum 2 weeks) of severe insomnia which is interfering with normal daily life and where other therapies (behavioural and pharmacologic) have failed. Chloral Hydrate Oral Solution is typically used as an adjunct to non-pharmacological therapies. Chloral Hydrate Oral Solution is also indicated for the short-term treatment (maximum 2 weeks) of severe insomnia in children and adolescents with suspected or definite neurodevelopmental disorder, when the insomnia is interfering with normal daily life and other therapies (behavioural and pharmacologic) have failed. The treatment is used as an adjunct to behavioural therapy and sleep hygiene management in children. Chloral hydrate has been used for a great many years as a sedative/hypnotic drug in human and veterinary medicine. The metabolite (trichloroethanol) is responsible for the pharmacological effect. The proposed mechanisms for the depression of the central nervous system include potentiating the function of GABAA receptors, inhibition of excitatory amino acid-activated currents mediated by A-m ethyl -D-aspartate, and allosteric modulation of the 5- hydroxytryptamine 3 receptor-mediated depolarization of the vagus nerve.

Chloral hydrate oral solution was first approved several years ago, but faced issues with respect to stability. It is known to undergo degradation upon storage, leading to formation of chloroform, which is a known carcinogen. It has been observed that while previously approved chloral hydrate oral solutions had an authorized shelf life of 18 months, that was reduced to 6 months in view of the amount of chloroform that was formed, despite storing the product at a temperature below 25 °C. Chloral hydrate solutions have also been available, and continue to remain available, as compounded medications, i.e. an oral solution of chloral hydrate is prepared by compounding pharmacies that are present in a hospital setting, or that provide the compounded product upon request to hospitals. While these compounded products have been touted to have the advantage of being available immediately upon request, and can be compounded at the desired concentration based on the need of the patient, what is detrimental is that these are possibly only tested as per the monograph requirements in the British Pharmacopoeia, i.e. only for assay of chloral hydrate. Thus, while the compounded chloral hydrate solution may have a “best before” date, there is no testing done to establish the content of chloroform and/or formic acid in the solution. Mostly, the compounded solutions are to be used within days of manufacturing. But in the absence of complete testing, even bulk solutions that test for only the assay of the solution (but do not test chloroform and formic acid), pose a risk in view of the degradation that may happen due to improper storage, such as at a higher temperature. Further, compounded products have the additional risk of being microbially contaminated if not prepared under GMP conditions. Thus, compounded chloral hydrate solutions have known disadvantages of low shelf life and untested levels of impurities, some of which may be carcinogenic, apart from the fact that there may be errors in dosing that may arise due to inefficient compounding. The health hazard from such use needs to be addressed on a high priority.

Luknitskii (Chemical Reviews, Vol 75, No 3, “The Chemistry of Chloral”, 259-289, Jun 1975) reported that the decomposition of chloral hydrate under the influence of strong alkalies, to form chloroform and formates, is common knowledge. The author reports that in spite of the stability of chloral hydrate, its solutions are not stable. On the one hand, this is connected with the hydration equilibrium; some researchers have recorded decomposition with elimination of water. On the other hand, chloral hydrate decomposes in neutral, acidic, and basic solutions. "Neutral" aqueous solutions are not stable for a long time; after 15 weeks the pH decreases from 6.72 to 4.75-2.33 (more in light and on cooling). UV irradiation accelerates this process; the pH decreases from 6.25 to 1.6 in 10 hr. The large decrease in pH of aqueous solutions of chloral hydrate on standing is the result of CCh-group destruction, with HC1 formation. The instability of chloral hydrate in alkaline solutions is well known. But most investigators have taken into account only the heterolysis of C-C bonds or have made their studies at such pH and temperature ranges that the other reaction - hydrolysis of the trichloromethyl group without C- C bond rupture - has been repressed almost completely. Bustos-Fierro et al (“Stability evaluation of 7% chloral hydrate syrup contained in mono and multi-dose bottles under room and refrigeration condition”, Farmacia Hospitalaria, 2013; 37(l):4-9) evaluates the stability of an extemporaneously prepared 7% chloral hydrate syrup under different conditions of storage and dispensing. The syrup is reported to contain refined sucrose, Alcohol 96%, sodium hydroxide 1.0 N and 0.1 N solutions and distilled water. The physical, chemical and microbiological stability was evaluated for 180 days. The chemical stability of the formulation was defined as “not less than 95% of the initial drug concentration remaining in the samples and a pH value not less than 2.05, the absence of visible particulate matter, or colour and/or odour changes and the compliance with microbiological attributes of non-sterile pharmaceutical products”. The authors refer to Kakehi et al (“Examination of the stability of chloral hydrate and its preparation by capillary electrophoresis”, Yakugaku Zasshi, Vol 119, No 5, pages 410-416, 1999) for teaching that the decrease in the pH of formulations of chloral hydrate can be used as an indicator of the degradation of the active principle (Kakehi et al showed that syrup and aqueous formulations of chloral hydrate are dependent on their pH for stability). The study reported in Bustos-Fierro et al concluded that extemporaneously compounded 7% chloral hydrate syrup was stable for at least 180 days when stored in mono- or multi-dose light-resistant glass containers at room temperature and under refrigeration, while the pH was maintained between 2.97 to 3.09. However, it must be noted that calculations indicate that 500mg/5ml solution of chloral hydrate may contain as high as 3800 ppm of chloroform, which is a reflection of the reported degradation of assay by 5%. So a solution that has assay meeting the “not less than 95%” specification could still contain a very large amount of chloroform. Nothing in Bustos-Fierro et al provides the reader with any teaching or suggestion regarding formulation of a chloral hydrate solution that can be stored over a longer period of time, such as 24 months, wherein the chloroform content would be within acceptable limits.

Thean et al (“Stability of extemporaneously compounded chloral hydrate oral solution”, Vol 4 No 1 (2018) Malaysian Journal of Pharmacy) studied the stability of Chloral Hydrate 40 mg per ml oral preparation formulated in X-temp Oral Suspension System in order to select proper storage conditions and establish beyond-use date. X-temp is an oral, flavoured sugar-free extemporaneous compounding vehicle used in the preparation of extemporaneous dosage forms, and in this case, a suspension formulation of chloral hydrate. The X-temp vehicle has an average pH of 4.1 (slightly acidic) and is buffered with the Citric Acid -Monosodium Phosphate buffering system. The chloral hydrate suspension thus prepared was stored in HDPE bottles. To be considered stable, the authors state the preparation had to retain a minimum of 90% of its initial drug dose and a pH value between 3.8 and 4.8. The analytic results reported in this study indicate that the chloral hydrate content in all samples assayed was above 99% throughout the 180 days period at 5 °C and 30 °C. However, it is well-known that chloroform will permeate out of HDPE bottles. Therefore, the preparation of Thean et al will likely have very low chloroform content due to physical permeation of the chloroform through the container. However, the authors state that the stability of the preparation is due to the compatibility of chloral hydrate with the X-Temp vehicle, and also because of the protective nature of the amber plastic container which prevents light degradation. The authors report that the nature of the X-temp vehicle ensures that the pH of the chloral hydrate solution remains slightly acidic and constant, which is favourable towards the stability of chloral hydrate. Thean et al reports that during the study, little or no chloral hydrate loss occurred in the samples for both storage conditions over 180 days. They report that the pH remained within the range of 3.8 to 4.1 and the assay was stable, which according to the authors, suggests minimal or no chemical degradation throughout the study period of 180 days. Further, nothing in Thean et al teaches or suggests means for obtaining a chloral hydrate solution that has a longer shelf life, such as up to 24 months, wherein the levels of chloroform are within acceptable limits.

CN 112656758 discloses a stable chloral hydrate syrup comprising chloral hydrate, cane sugar and water, wherein the mass volume concentration of chloral hydrate is 10%, and the pH value of the chloral hydrate syrup is 2.3-3.0. The inventors state that stability of chloral hydrate is very poor, and is greatly influenced by temperature, illumination and solution pH value. The patent application states that chloral hydrate syrup prepared in hospitals has no systematic impurity research, and particularly, research reports on generated 5-hydroxymethylfurfural (degradation product of the syrup in the composition) and toxic chloroform (trichloromethane) are not carried out. The applicants conducted systematic studies on the formulation of chloral hydrate syrups and found that the stability of chloral hydrate decreased with increasing acidity of the solution, with chloral hydrate degrading to toxic chloroform at higher pH, whereas sucrose in syrup is converted to toxic 5-hydroxymethylfurfural. Therefore, the control range of the pH of the chloral hydrate syrup was stated to be the key for determining the quality of the chloral hydrate syrup. The publication states that when the pH value of the chloral hydrate syrup is between 2.3 to 3.0, the long-term stability is good, and the chloroform (not more than 0.06%) and the 5-hydroxymethylfurfural (not more than 0.5%) can be controlled within the allowable range of the pharmacopoeia. The publication also provides comparison of the stability of their composition with two compounded preparations of chloral hydrate available from local hospitals, both of which were 10% chloral hydrate oral liquids with pH 3.84 and pH 3.46, respectively. All three products were stored at 60 °C for 30 days and at 40 °C for 30 days, and stability was investigated by testing the amount of chloroform formed. The publication reports that while the compounded hospital products degraded significantly to form more than 0.4% of chloroform, the chloral hydrate syrup containing glycerol and having a pH of 2.3 to 3.0 was found to have chloroform content below 0.06%. However, there is no disclosure on the shelf life of the chloral hydrate composition, and certainly no detailing on how to obtain a product that is stable for up to 24 months or more. This publication in fact teaches that higher pH, such as that of the compounded hospital products, provides an unstable product.

CN 110151687 discloses a chloral hydrate solution concentrate, which comprises chloral hydrate, a pharmaceutically acceptable acid and water, wherein the mass concentration of the chloral hydrate is 40-80%, and the pH value of the chloral hydrate solution is preferably between pH 1.0 to pH 2.9. From the results shown in figure 1 of this publication, it is understood that the amount of chloroform increases as the pH of the chloral hydrate solution increases. When the pH of the chloral hydrate solution is greater than 2.9, the amount of chloroform produced was shown to increase sharply with an increase in the pH of the chloral hydrate solution. Therefore, the publication teaches that a lower pH is advantageous for improving the stability of chloral hydrate, and the product has been reported to have a shelflife of 24 months, wherein the amount of chloroform in the product does not exceed 0.06%. However, such a chloral hydrate solution having lower pH value and higher concentration was reported to have poor taste and certain irritation, thereby making it unsuitable for oral administration.

Both the above Chinese publications refer to literature reports that teach use of an inclusion compound like beta-cyclodextrin with chloral hydrate oral solution to improve stability. However, the effective period or shelf life of the product was reported to be prolonged to only 46.63 days. Similarly, other references reported chloral hydrate syrup with pH of 4.21 to 4.77, but no reported improvement in shelf life of the product.

Uriel et al (“Stability of regularly prescribed oral liquids formulated with SyrSpend® SF, Pharmazie 73: 196-201 (2018)) discloses a chloral hydrate composition of 100.0 mg/ml in SyrSpend SF liquid, which is buffered to pH 4.2. The ingredients of SyrSpend SF are purified water, modified food starch, sodium citrate, citric acid, sucralose, sodium benzoate (<0.1 %, preservative), malic acid and simethicone, as reported by Uriel et al. Table 4 of this reference provides stability assay of the SyrSpend SF formulations, stored at both controlled room temperature and refrigerated condition. Acceptance criteria were: 90-110% of initial concentration at time 0. It can be seen that the chloral hydrate formulation is reported to have a drug recovery of 88.1% at the end of 90 days of storage at room temperature, and a drug recovery of 88.4% at the end of 90 days of storage under refrigeration. The chloral hydrate would therefore, fail the acceptance criteria at 90 days, making the product unsuitable for use after 90 days of storage. The results in Table 4 indicate that a beyond-use date of 60 days can be assigned to chloral hydrate 100.0 mg/ml, as the drug recovery at the end of 60 days is91.8% and 92.1% at room temperature and under refrigeration, respectively. Thus, Uriel et al only discloses a chloral hydrate formulation that can be best used for 60 days - it cannot be used beyond that, and nothing in Uriel et al teaches compositions of chloral hydrate that are stable over longer periods of time, such as over 12 or 24 months.

GB1421144 of E R Squibb and Sons Inc., discloses one piece gelatin capsules containing chloral hydrate, wherein the chloral hydrate is included in a non-aqueous carrier. The inventors considered that, in spite of the substantial absence of water from the formulations encapsulated, sufficient water is inevitably present in the system, e.g. in the material of the capsule, to effect some hydrolysis of the chloral hydrate to produce trichloroacetic and/or hydrochloric acids which then attack the gelatin, leading to leakage of the capsule. With this in mind they prepared substantially water-free chloral hydrate formulations containing a buffering agent for maintaining the pH within the range 4 to 7 and found that when these were encapsulated in one-piece gelatin capsules in non-aqueous carrier, there was little tendency for leakage to occur. There is nothing in this reference that teaches aqueous formulations of chloral hydrate that are stable over longer periods of time, such as 24 months or longer, wherein the amount of chloroform is within acceptable limits.

The applicants of the present application previously marketed chloral hydrate solutions under the brand name Welldorm Elixir, 143mg/5mL, that was a red-coloured, unbuffered solution (originally marketed by Smith & Nephew, that Marlborough Pharmaceuticals acquired). Later, an additional strength of 500mg/5mL was developed to meet requirements at hospitals, which was similar in composition to the original Welldorm Elixir, except that it was a colourless (no azo dye) solution, buffered with Citric acid : Sodium citrate. This buffered solution had a shelf- life of less than 12 months, as the content of chloroform exceeded the acceptable limits within 9 months or so. Thus, there is a need for a chloral hydrate aqueous solution that is stable over a longer period of time, such as 24 months or more, wherein the content of chloroform in the solution is within acceptable limits at the end of shelf-life.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a chloral hydrate solution comprising chloral hydrate in an amount ranging from about 20mg/ml to about lOOmg/ml and one or more pharmaceutically acceptable buffers such that the solution is buffered between; a pH of about 3.2 to about 4.5.

In some embodiments, the present invention provides a chloral hydrate solution comprising chloral hydrate in an amount ranging from about 20mg/ml to about lOOmg/ml and one or more pharmaceutically acceptable excipients; wherein the solution has a pH of about 3.2 to about 4.5; such that the solution has no more than 300 ppm of chloroform, no more than 800 ppm of formic acid, and no more than 100 ppm of monochloroacetaldehyde, when stored at 25 °C, 60% relative humidity for 9 months.

Suitably, the chloral hydrate solution is an oral chloral hydrate solution.

In some embodiments, the solution has a pH of about 3.7 to about 4.5. In some embodiments, the solution has a pH of about 4.1 to about 4.4.

In some embodiments, the solution has a pH of 3.2 to 4.5. In some embodiments, the solution has a pH of 3.7 to 4.5. In some embodiments, the solution has a pH of 4.1 to 4.4.

In some embodiments, the chloral hydrate solution further comprises one pharmaceutically acceptable excipient. In some embodiments, the chloral hydrate solution further comprises more than one pharmaceutically acceptable excipient. In some embodiments, the chloral hydrate solution further comprises one, two, three, four, five, six, seven, eight or more pharmaceutically acceptable excipients.

In some embodiments, the one or more pharmaceutically acceptable excipients further includes a pH adjusting agent, diluent, sweetener, flavouring agent and antimicrobial agent. The chloral hydrate solution comprises a buffer. In some embodiments, the chloral hydrate solution comprises a buffer, such that the solution is buffered between a pH of about 3.2 and about 4.5. In some embodiments, the chloral hydrate solution comprises a buffer, such that the solution is buffered between a pH of 3.2 and 4.5. In some embodiments, the chloral hydrate solution comprises a buffer, such that the solution is buffered between a pH of about 3.7 and about 4.5. In some embodiments, the chloral hydrate solution comprises a buffer, such that the solution is buffered between a pH of 3.7 and 4.5. In some embodiments, the chloral hydrate solution comprises a buffer, such that the solution is buffered between a pH of about 4.1 and about 4.4. In some embodiments, the chloral hydrate solution comprises a buffer, such that the solution is buffered between a pH of 4.1 and 4.4.

In some embodiments, the chloral hydrate solution comprises a buffer and one or more further pharmaceutically acceptable excipients, optionally selected from a diluent, sweetener, flavouring agent and antimicrobial agent. Preferably, the buffer is selected from citrate, acetate, phosphate and mixtures thereof.

In some embodiments, the buffer is a mixture of an acid, and a salt in a ratio of about 60:40 to about 90: 10 by weight. In some embodiments, the buffer is a mixture of an acid, and a salt in a ratio of about 65:35 to about 90: 10 by weight. In some embodiments, the buffer is a mixture of an acid, and a salt in a ratio of about 70:30 to about 90:10 by weight. In some embodiments, the buffer is a mixture of an acid, and a salt in a ratio of about 80:20 to about 90: 10 by weight, In some embodiments, the buffer is a mixture of an acid, and a salt in a ratio of about 60:40 to about 85: 15 by weight. In some embodiments, the buffer is a mixture of an acid, and a salt in a ratio of about 65:35 to about 85: 15 by weight. In some embodiments, the buffer is a mixture of an acid, and a salt in a ratio of about 60:40 to about 82:18 by weight. In some embodiments, the buffer is a mixture of an acid, and a salt in a ratio of about 65:35 to about 82: 18 by weight. In some embodiments, the buffer is a mixture of an acid, and a salt in a ratio of about 70:30 to about 82: 18 by weight. In some embodiments, the buffer is a mixture of an acid and a salt in a ratio of about 60:40 to about 82: 18 by weight.

In some embodiments, the buffer is a mixture of citric acid and sodium citrate, preferably in a ratio of about 60:40 to about 90: 10 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of about 65:35 to about 90:10 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of about 60:40 to about 85: 15 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of about 65:35 to about 85: 15 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of about 60:40 to about 82: 18 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of about 65:35 to about 82: 18 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of about 70:30 to about 82: 18 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of about 60:40 to about 82: 18 by weight.

In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 60:40 to 90: 10 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 65:35 to 90: 10 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 60:40 to 85: 15 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 65:35 to 85: 15 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 60:40 to 82: 18 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 65:35 to 82: 18 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 70:30 to 82: 18 by weight. In some embodiments, the buffer is a mixture of citric acid and sodium citrate in a ratio of 60:40 to 82: 18 by weight.

In some embodiments, the buffer is a mixture of acetic acid and sodium acetate. In some embodiments, the buffer is a mixture of citric acid and disodium hydrogen phosphate. In some embodiments the buffer is a mixture of disodium phosphate and sodium dihydrogen phosphate.

In some embodiments, the chloral hydrate solution comprises a pH adjusting agent. In some embodiments, the chloral hydrate solution comprises a pH adjusting agent, such that the solution has a pH of about 3.2 to about 4.5. In some embodiments, the chloral hydrate solution comprises a pH adjusting agent, such that the solution has a pH of 3.2 to 4.5. In some embodiments, the chloral hydrate solution comprises a pH adjusting agent, such that the solution has a pH of about 3.7 to about 4.5. In some embodiments, the chloral hydrate solution comprises a pH adjusting agent, such that the solution has a pH of 3.7 to 4.5. In some embodiments, the chloral hydrate solution comprises a pH adjusting agent, such that the solution is has a pH of about 4.1 to about 4.4. In some embodiments, the chloral hydrate solution comprises a pH adjusting agent, such that the solution has a pH of 4.1 to 4.4.

In some embodiments, the chloral hydrate solution comprises a pH adjusting agent and one or more further pharmaceutically acceptable excipients, optionally selected from a diluent, sweetener, flavouring agent and antimicrobial agent. Preferably, the buffer is selected from citrate, acetate, phosphate and mixtures thereof.

In some embodiments, the pH adjusting agent is selected from hydrochloric acid, a water soluble organic acid and mixtures thereof. In some embodiments, the pH adjusting agent is hydrochloric acid. In some embodiments, the pH adjusting agent is a water soluble organic acid. In some embodiments, the pH adjusting agent is a mixture of water soluble organic acids. In some embodiments, the pH adjusting agent is a mixture of hydrochloric acid and one or more water soluble organic acids.

In some embodiments, the chloral hydrate solution comprises a diluent. Preferably, the diluent is selected from water, alcohol, liquid glucose, syrup, sorbitol, glycerol, propylene glycol, polyethylene glycol and mixtures thereof. In some embodiments the diluent is water.

In some embodiments, the chloral hydrate solution comprises a sweetener. Preferably, the sweetener is selected from agave nectar, brown rice syrup, hydrogenated glucose syrup, date sugar, honey, molasses, blackstrap molasses, sorghum syrup, stevia, maple syrup, birch syrup, yacon syrup, lucuma powder, coconut sugar, erythritol, maltitol, mannitol, sorbitol, xylitol, isomalt crystals, lactitol, maltitol, acesulfame, advantame, alitame, allulose, aspartame, neotame, saccharin, sodium saccharin, sucralose, acesulfame potassium, tagatose, thaumatin, stevioside and mixtures thereof.

In some embodiments, the chloral hydrate solution comprises a flavouring agent. Preferably, the flavouring agent is selected from almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, mango, grape, grapefruit, guava, hop, lemon, licorice, lime, elderberry, malt, mandarin, molasses, nutmeg, mixed berry, orange, peach, pear, peppermint, pomegranate, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla, winter green, tutti-frutti, bubblegum and mixtures thereof. In some embodiments, the chloral hydrate solution comprises an antimicrobial agent. Preferably, the antimicrobial agent is selected from benzoic acid, methyl paraben, propyl paraben, butyl paraben, sorbic acid and their pharmaceutically acceptable salts, and mixtures thereof.

In some embodiments, the choral hydrate solution has no more than 300 ppm of chloroform, no more than 800 ppm of formic acid and no more than 100 ppm of monochloroacetaldehyde for 24 months when stored below 25 °C.

In some embodiments, the chloral hydrate is present in an amount of 450 to 550 mg/5ml, more preferably 475 to 525 mg/5ml, even more preferably 490 to 510 mg/5ml, and most preferably about 500mg/5ml. In some embodiments, the chloral hydrate is present in an amount of 500mg/5ml.

In other embodiments, the chloral hydrate is present in amount of 120 to 160 mg/5ml, more preferably 130 to 155 mg/5ml, even more preferably 135 to 150 mg/5ml, and most preferably about 143 mg/5ml.

In a second aspect, the present invention provides the chloral hydrate solution of the first aspect for use in a method of treatment of the human or animal body. The second aspect also provides the use of the chloral hydrate solution of the first aspect in a method of treatment of the human or animal body.

In a third aspect, the present invention provides the chloral hydrate solution of the first aspect for use in the treatment of insomnia. The third aspect also provides the use of the chloral hydrate solution of the first aspect in a method of treating insomnia. Also provided is the use of the chloral hydrate solution of the first aspect in the manufacture of a medicament for the treatment of insomnia.

In a fourth aspect, the present invention provides the chloral hydrate solution of the first aspect for use in a method of sedating a subject. The fourth aspect also provides the use of the chloral hydrate solution of the first aspect in a method of sedating a subject. Also provided is the use of the chloral hydrate solution of the first aspect in the manufacture of a medicament for sedating a subject. Preferably the subject is a pediatric patient.

In the second, third and fourth aspects of the invention, the chloral hydrate solution is preferably administered orally.

In a fifth aspect, the present invention provides a method of preparing the chloral hydrate solution of the first aspect, comprising mixing the chloral hydrate with the one or more pharmaceutically acceptable excipients in an aqueous solution.

The invention includes the combination of the aspects and preferred features described, except where such a combination is clearly impermissible or expressly avoided.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a stable oral chloral hydrate solution comprising chloral hydrate in an amount ranging from about 20mg/ml to about lOOmg/ml and pharmaceutically acceptable excipients, wherein the pH of the solution ranges from about 3.2 to about 4.5, and wherein the solution has a shelf life of at least 24 months, such that the solution has no more than 300ppm of chloroform and no more than 800ppm of formic acid, when stored below 25°C.

Chloral Hydrate 500mg/5ml Oral Solution of the present invention is to be administered as a single daily dose, between 15 to 30 minutes before bedtime with water or milk. The usual dose in adults is 430-860 mg (4.3-8.6 ml of the 500mg/5ml strength). Higher doses should not exceed a maximum of 2 g chloral hydrate (20 ml of the 500mg/5ml strength) per dose. In children 12 years and over, the usual dose is 430-860 mg (4.3-8.6 ml of the 500mg/5ml strength). Higher doses should not exceed a maximum of 2 g chloral hydrate (20 ml of the 500mg/5ml strength) per dose. In children between 2 and 11 years of age, the dose is 30-50 mg/kg (0.3-0.5 ml/kg of the 500mg/5ml strength) of bodyweight. The dose should not exceed 1 g chloral hydrate (10 ml of the 500mg/5ml strength) per dose.

Scheme 1 shows a simplified chemical equation for the degradation of chloral hydrate to form equimolar amounts of chloroform and formic acid.

Chloral hydrate Chloroform Formic acid

Scheme 1

The exact mechanism is still not fully understood in the scientific literature, although the formation of chloroform and formic acid is well established. This is essentially a hydrolysis degradation mechanism, i.e. the addition of a water molecule across the carbon-carbon backbone splits the chloral hydrate into the equimolar, individual components of chloroform and formic acid. Like all hydrolytic degradation processes, the rate of this reaction is also dependent on the physical and chemical environment in which the chloral hydrate is present.

The present inventors have previously worked on a chloral hydrate solution of strength 143mg/5ml, which was commercially available. A review of the development work performed on the Chloral hydrate 143mg/5 ml oral solution highlighted that chloral hydrate API (active pharmaceutical ingredient) itself has a natural acidic pH (the European Pharmacopoeia monograph highlights an aqueous solution pH of 3.5 - 5.5 for a 10 % w/v solution of the API dissolved in carbon dioxide free-water). The chloral hydrate API is freely soluble in water, but it is susceptible to a degradation pathway leading to formation of equimolar quantities of chloroform and formic acid. Hence, the natural pH of the API dissolved in water actually catalyses the degradation mechanism. The aqueous based oral solution of chloral hydrate is thus exposed to a self-perpetuating degradation process. Upon manufacture of the oral solution, when the API is dissolved in water, the hydrolysis degradation mechanism is initiated. The thermal conditions were found to enhance the degradation mechanism pathway but do not initiate the degradation itself, as water is the primary initiator.

The original formulation of 143mg/5ml oral solution was manufactured as an unbuffered formulation. The natural pH of this unbuffered oral solution was about 6.1-6.2 upon manufacture, and the rate of degradation was observed to be fast at this particular pH. As the oral solution continued to degrade, the amount of formic acid increased. There was a subsequent drop in pH of the solution, and eventually the rate of chloroform formation was observed to have decreased. Therefore, the conclusion was that the more acidic the oral solution, the better the observed stability, in terms of the chloroform formation. pH development trial batches of the 143mg/5ml formulation were conducted which showed that the addition of an acidic buffer system stabilised the finished product, leading to a reduced rate of chloroform formation. The solution was reformulated by addition of a combination of citric acid and sodium citrate in a 60:40 ratio and adjusting the pH between 4.5 and 6.5. This solution was commercialized with a shelflife of one year (unopened bottle) and 28 days (opened bottle), when stored below 25 °C. However, it was later discovered that the amount of chloroform increased in the solution such that the levels were much higher than the ICH residual solvent limit for chloroform of 300 ppm. Accordingly, the shelf life of the 143mg/5ml oral solution had to be revised and reduced to 6 months (unopened bottle) and 28 days (opened bottle), when stored below 25 °C. The root cause for this increased degradation was found to be the pH of the solution, which was due to the insufficient buffering capacity of the buffer used.

The pH of the liquid medium containing the chloral hydrate is a very pertinent characteristic of the hydrolytic degradation it can undergo. In summary, the hydrolysis rate of degradation is controlled by the ambient pH and storage temperature. The degradation of the chloral hydrate API in the aqueous oral solution cannot be chemically stopped (unless it is in a fully nonaqueous matrix), but it can be controlled by the chemical (pH) and physical (temperature) environment. Therefore, stressing study conditions such as thermal conditions, which enhance this degradation mechanism were used as accelerated stability conditions to conduct studies and determine the pH at which the solution would be stable and provide the desired shelf life of the chloral hydrate solution. The pH that provides optimum stability of the oral solution of the present invention was determined through various experiments. The term “pH that provides optimum stability” means a pH suitable for oral administration, i.e. not too acidic to impact taste, nor alkaline to cause degradation of the chloral hydrate, the target being a stable solution of chloral hydrate. The term “stable” as used herein refers to an oral chloral hydrate solution with not more than 300 ppm of chloroform and not more than 800 ppm of formic acid at the end of at least 12 months, upon storage of the solution below 25 °C. In preferred embodiments the chloral hydrate solution of the present invention is stable for at least 24 months.

The present invention provides a stable solution of chloral hydrate wherein the content of chloroform is within acceptable limits, i.e., not more than 300ppm of chloroform is present in the solution at the end of at least 12 months, preferably at least 24 months, upon storage of the solution below 25°C. In the oral chloral hydrate solution of the present invention, the chloroform specification is set at “not more than 300 ppm”, which relates to the ICH Residual Solvent specification for this Class II solvent. The chloroform compound itself is not a residual solvent as such in this product, but as discussed above, it is a potential degradation product in the finished product, i.e. the oral solution. Similarly, the specification for formic acid, which is also a degradation product of chloral hydrate, is set at “not more than 800 ppm” which is below the ICH Residual Solvent specification of 5000 ppm for this Class III solvent.

Chloral hydrate API may contain monochloroacetaldehyde (commonly referred to as MCAT or MCAA) as a process impurity. MCAT is mutagenic or carcinogenic in nature. This impurity must be controlled so that the finished dosage form, i.e. the oral solution, has levels of MCAT that are within acceptable limits. Further, the pharmaceutically acceptable excipients used in the formulation of the oral solution should not cause increase of MCAT upon storage. The MCAT may not be present in an amount more than 100 ppm in the oral solution at the end of shelf life.

The term “shelf life” as used herein refers to the amount of time the pharmaceutical composition may be stored without loss of potency and/or performance profile. In other words, shelf life refers to the amount of time the composition may be stored without formation of chloroform in an amount exceeding 300ppm and formic acid in an amount more than 800ppm, when stored at room temperature. An ideal shelf life for the chloral hydrate solution would be at least 12 months or more. A stable chloral hydrate oral solution that has not more than 300 ppm of chloroform, not more than 800 ppm of formic acid and not more than 100 ppm of MCAT at the end of at least 24 months from manufacturing, would be commercially viable and desirable. As discussed above, the prior art suggests use of pH over a wide range. While chloral hydrate solutions with pH between 3-5 were reported to have a shelf life of merely 180 days, some others with pH lower than 3 were found to be highly acidic, irritating and with a bad taste. Though the degradation of chloral hydrate to chloroform was known in the art, there was nothing in the prior art that provided a teaching, suggestion or motivation to obtain a stable product, as described herein, with a shelf life of at least 12 months or more, and which would not have issues related to taste. In preferred embodiments, the stable compositions provided herein are designed to have shelf life of at least 24 months. The present invention provides a stable chloral hydrate oral solution having a pH of about 3.2 to about 4.5. The pH range of about 3.2 to about 4.5 is critical and was surprisingly found by the present applicants to provide a stable solution with a long shelflife of at least 12 months or more, wherein the levels of chloroform and formic acid in the solution are controlled, when stored below 25 °C.

In a highly preferred embodiment of the present invention the oral chloral hydrate solution has a pH of about 3.2 to about 4.5 and is stable for a period of at least 24 months, when stored below 25 °C.

The pharmaceutically acceptable excipients used in the chloral hydrate solution of the present invention are those that are conventionally used in oral solutions, and are well known to persons of skill in the art of formulating oral dosage forms. So long as the pH of the solution is maintained between about 3.2 to about 4.5, the use of conventional excipients is found to be permissible.

The applicants of the present invention conducted trial batches with different ratios of the citric acid : sodium citrate buffer, such as 60:40, 70:30 and 82: 18 for the 143mg/5ml strength, wherein the chloral hydrate solution was found to have pH in the range of about 3.2 to about 4.5. These buffered solutions were subjected to stability studies and tested for levels of chloroform and formic acid. The acceptable conditions were that the chloral hydrate solution should have not more than 300 ppm of chloroform and not more than 800 ppm of formic acid at the end of the desired shelf life, i.e. when stored under accelerated storage conditions, the results obtained at the end of the testing period must extrapolate to a shelf-life of at least 24 months. The stability studies were carried out under two conditions - (i) 25°C / 60% relative humidity (RH), and (ii) 30°C / 65% RH, and the products were tested at the end of 3, 6 and 9 months of storage.

Generally, any buffer that maintains the pH of the chloral hydrate solution in the range of about 3.2 to about 4.5 may be used. The term “maintains the pH”, as used herein, essentially means that the amount and type of buffer used is such that the target pH - about pH 3.2 to about pH 4.5 as used for the solution of the present invention - does not deviate over the shelf life, i.e. the difference in pH upon manufacturing and at the end of shelflife does not vary by more than 10%. Thus, a stable solution of chloral hydrate can be achieved by using the appropriate quantity of buffer and buffer components, such that the pH is maintained in the range of about 3.2 to about 4.5 over the shelflife. This pH range may be achieved by using a suitable buffering capacity. Examples of buffers that may be used in the oral chloral hydrate solution of the present invention include, but are not limited to, citrate, acetate, phosphate and mixtures thereof. Alternatively, the pH may be adjusted to the desired range of about 3.2 to about 4.5 with a suitable amount of a pH adjusting agent such as hydrochloric acid, water-soluble organic acids, and mixtures thereof. Examples of pH adjusting agents include, but are not limited to, hydrochloric acid, citric acid, tartaric acid, malic acid, maleic acid, succinic acid, lactic acid, their pharmaceutically acceptable salts and mixtures thereof. Typically, 0. IN hydrochloric acid solution may be used.

The oral chloral hydrate solution of the present invention may include one or more of a diluent, sweetener, flavouring agent, antimicrobial agent (preservative). These are typically selected from the excipients conventionally used in the art and known to a person of skill in the art of formulating oral dosage forms.

Typical diluents that may be used include, but are not limited to, water, alcohol, liquid glucose, syrup, sorbitol, glycerol, propylene glycol, polyethylene glycol and mixtures thereof. The diluent is typically used in amount ranging from about 5% v/v to about 95% v/v.

Sweeteners that may be used in the oral chloral hydrate solution of the present invention may be selected from nutritive sweetening agents, non-nutritive sweetening agents and mixtures thereof. The nutritive sweetening agents may be selected from, but are not limited to, agave nectar, brown rice syrup, hydrogenated glucose syrup, date sugar, honey, molasses and blackstrap molasses, sorghum syrup, stevia, maple syrup, birch syrup, yacon syrup, lucuma powder, coconut sugar, erythritol, maltitol, mannitol, sorbitol, xylitol, isomalt crystals, lactitol, maltitol and mixtures thereof. The non-nutritive sweetening agents may be selected from, but are not limited to, acesulfame, advantame, alitame, allulose, aspartame, neotame, saccharin, sodium saccharin, sucralose, acesulfame potassium, tagatose, thaumatin, stevioside and mixtures thereof. The sweetener may be used in an amount ranging from about 0.02% to about 70%. In some embodiments, the oral chloral hydrate solution only contains artificial sweeteners and is sugar free. A flavouring agent or flavourant can be added to enhance the taste or aroma of the oral chloral hydrate solution of the invention. Non-limiting examples of suitable natural flavours, some of which can readily be simulated with synthetic agents or combinations thereof, include almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, mango, grape, grapefruit, guava, hop, lemon, licorice, lime, elderberry, malt, mandarin, molasses, nutmeg, mixed berry, orange, peach, pear, peppermint, pomegranate, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla, winter green, and the like, as well as combinations thereof. Also useful, particularly where the formulation is intended primarily for pediatric use, is tutti-frutti or bubblegum flavour and/or a compounded flavouring agent based on fruit flavours. Presently preferred flavouring agent is essence of passion fruit. The flavouring agent may be used in an amount ranging from about 0.3% to about 5%.

Typical antimicrobial agents or preservatives that may be used in the oral chloral hydrate solution of the present invention include, but are not limited to, benzoic acid, methyl paraben, propyl paraben, butyl paraben, sorbic acid and their pharmaceutically acceptable salts, and mixtures thereof. The preservative may be present in an amount ranging from about 0.01% to about 3%.

The oral chloral hydrate solution of the present invention can be prepared by processes conventional in the art and known to those of skill in the art. These have been elaborated in the examples provided below.

The oral solutions of the present invention may be stored in amber glass bottles with screw cap made of polypropylene/HDPE/LDPE, and may be presented in a carton. Each pack may contain a 5 ml oral syringe having a polypropylene body and a HDPE plunger, with intermediate graduations of 0.1 ml, and a syringe adapter made of LDPE.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description of the disclosure herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For the avoidance of any doubt, any theoretical explanations provided herein are provided for the purposes of improving the understanding of a reader. The inventors do not wish to be bound by any of these theoretical explanations.

The features disclosed in the foregoing description or in the following claims, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for obtaining the disclosed results, as appropriate, may, separately or in any combination of such features, be utilised for realising the invention in diverse forms thereof. Unless the context indicates otherwise, it is specifically intended that the various features of the disclosure described herein can be used in any combination.

Moreover, the present disclosure also contemplates that in some embodiments of the disclosure, any feature or combination of features set forth herein can be excluded or omitted. While the invention has been described in conjunction with the exemplary embodiments described herein, many equivalent modifications and variations will be apparent to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments of the invention set forth herein are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the invention.

All publications, patent applications, patents, and other references mentioned herein are incorporated by reference herein in their entirety for all purposes.

Any section headings used herein are for organisational purposes only and are not to be construed as limiting the subject matter described.

As used herein, “ppm” refers to parts per million by weight.

Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise” and “include”, and variations such as “comprises”, “comprising”, and “including” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

It must be noted that, 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. Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment. The term “about” in relation to a numerical value (as used herein when referring to a measurable value such as an amount of a compound or agent of this disclosure, dose, time, temperature, pH and the like) is optional and means for example +/- 20%.

Also as used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

The term “solution”, “composition” and “formulation” may be used interchangeably herein.

EXAMPLES

Example 1

Purified Water and Glycerol were mixed for a minimum of 10 minutes until fully dispersed. Chloral Hydrate, Sodium Benzoate and Sodium Saccharin were then added while mixing continuously for a minimum of 30 minutes until fully dissolved to obtain a bulk solution. Citric acid and Sodium Citrate were dissolved in purified water in a separate container. This solution was added to the bulk solution and mixed for a minimum of 10 minutes until fully dispersed. Liquid Glucose was warmed to 45 °C and added to the above solution and mixed continuously for a minimum of 15 minutes until fully dispersed. Passion Fruit Essence was then added and mixed for 30 minutes until fully dispersed. The solution thus obtained was filtered through stainless steel filters and filled in bottles. The final solution has a pH of 4.4.

Example 2

The chloral hydrate solution obtained in Example 1 was subjected to stability testing at accelerated conditions mentioned in the table below, and the product was tested at 3 months and 6 months. The results of the stability test are included in Table 1 below.

Table 1

As can be seen in the table above, the chloral hydrate solution of Example 1, which contains citric acid - sodium citrate in a 70:30 ratio, has less than 300 ppm of chloroform at the end of 6 months when stored at the accelerated conditions, indicating that the product would have a shelf life of more than 6 months when stored below 25 °C.

Example 3

The chloral hydrate solution was obtained by the process described in Example 1 above, as a 50 liter batch. The oral solution contains citric acid - sodium citrate in an 82: 18 ratio, and the solution has a pH of 4.1.

Example 4

The chloral hydrate solution obtained in Example 3 was subjected to stability testing at accelerated conditions mentioned in the table below, and the product was tested at 6 months and 9 months. The results of the stability test are included in Table 2 (bottles stored in upright position) and Table 3 (bottles stored in inverted position).

Table 2

Table 3

As can be seen in Tables 2 and 3 above, the chloral hydrate solution of Example 3, which contains citric acid - sodium citrate in an 82: 18 ratio, has less than 300 ppm of chloroform and less than 800 ppm of formic acid at the end of 9 months when stored at the intermediate accelerated conditions, indicating that the product would have a shelflife of at least 24 months when stored below 25 °C.

Example 5

An additional 50 liter batch, similar in composition to Example 3, was executed and the solution thus obtained was subjected to stability testing at accelerated conditions. The results of the testing are included in Table 4 (bottles stored in upright position) and Table 5 (bottles stored in inverted position). Table 4

Table 5

As can be seen in Tables 4 and 5 above, the chloral hydrate solution has less than 300 ppm of chloroform and less than 800 ppm of formic acid at the end of 9 months when stored at the accelerated conditions, indicating that the product would have a shelflife of at least 24 months when stored below 25 °C.

Example 6

A chloral hydrate solution of strength 143mg/5ml was prepared using the above inactive ingredients, using a process similar to that disclosed in Example 1 above. The solution above used a citric acid : sodium citrate ratio of 82: 18. Similar solutions using citric acid : sodium citrate ratios of 60:40 and 70:30 were also prepared using a similar process. The pH of the solutions was found to be about 3.2 to about 4.5. All solutions were found to be stable when stored at 25°C, 60% relative humidity, over a period of 6 months. The chloroform content in these solutions was found to stay below 300 ppm at the end of 6 months. An extrapolation of the data indicates that the shelf life of the solution was at least 24 months.

Example 7

The test solutions were prepared as aliquots from a bulk solution of Chloral hydrate dissolved in Purified Water to a concentration of 500 mg / 5 mL. Each 20 mL aliquot of the bulk solution was then buffered with a further 1 mL of buffer components. The various buffers used were -

• Acetate Buffer : 0.2M Acetic acid : 0.2M Sodium acetate

• Citric acid / Phosphate Buffer : 0.2M Citric acid : 0.2M Disodium hydrogen phosphate (also called Sodium phosphate dibasic)

• Phosphate Buffer : 0.2M Disodium hydrogen phosphate : 0.2M Sodium dihydrogen phosphate (pH adjusted to target pH with IM Phosphoric acid).

The table below provides the various solutions prepared. ‘Acetate Buffer 90: 10’ signifies that the aliquot of Chloral hydrate bulk solution was buffered with 90 % of 0.2M Acetic acid (i.e. 0.9 mL) and 10 % of 0.2M Sodium Acetate (i.e. 0.1 mL). Similarly, the other buffers were prepared and added.

* Chloroform and Formic acid are degradation products derived from Chloral hydrate, formed in a 1: 1 mole ratio. Therefore, the content of Chloroform is a constant factor multiple of the Formic acid content, and vice-versa. The mole ratio factor is formally calculated as 2.597 : 1, or more simply 2.6 : 1 (Chloroform to Formic acid), hence any Formic acid (ppm) content can be multiplied by ‘2.6’ to provide a corresponding theoretical, but analytically valid, Chloroform content (ppm). The Formic acid has a much higher boiling point compared to Chloroform, therefore it does not encounter the same volatility issues encountered by the Chloroform degradation product within the sample containers, and hence the need to calculate the Chloroform content on the basis of the formic acid content As can be seen above, in the high pH solutions A-D, the pH dropped during the 5 week period, and the chloroform and formic acid content went up accordingly. The high pH led to increased degradation of chloral hydrate, and the buffer capacities of the solutions A-D being insufficient to maintain the pH over the storage period, the pH dropped. However, for solutions E-I, the acidic pH was maintained and the chloroform and formic acid contents remained significantly low. Since the buffer capacities for solutions E-I was sufficient, the pH was consistently maintained, and the degradation was very low.

Claims

1. A chloral hydrate solution comprising chloral hydrate in an amount ranging from about 20mg/ml to about lOOmg/ml and one or more pharmaceutically acceptable buffers such that the solution is buffered between a pH of about 3.2 to about 4.5.

2. The chloral hydrate solution of claim 1 wherein the solution has a. no more than 300 ppm of chloroform, b. no more than 800 ppm of formic acid and c. no more than 100 ppm of monochloroacetaldehyde, when stored at 25 °C, 60% relative humidity for 9 months.

3. The chloral hydrate solution of either claim 1 or claim 2 wherein the solution further includes one or more of a pH adjusting agent, diluent, sweetener, flavouring agent and antimicrobial agent.

4. The chloral hydrate solution of claim 1 wherein the solution is buffered between a pH of about 3.7 and about 4.5.

5. The chloral hydrate solution of claim 1 wherein the solution is buffered between a pH of about 4.1 and about 4.4.

6. The chloral hydrate solution of any one of claim 1 wherein the buffer is selected from citrate, acetate, phosphate and mixtures thereof.

7. The chloral hydrate solution of claim 6 wherein the buffer is a mixture of citric acid and sodium citrate.

8. The chloral hydrate solution of claim 7 wherein the buffer is a mixture of citric acid and sodium citrate in a ratio of about 60:40 to about 90: 10 by weight.

9. The chloral hydrate solution of claim 8 wherein the buffer is a mixture of citric acid and sodium citrate in a ratio of about 65:35 to about 90: 10 by weight.

10. The chloral hydrate solution of claim 8 wherein the buffer is a mixture of citric acid and sodium citrate in a ratio of about 60:40 to about 82: 18 by weight.

11. The chloral hydrate solution of claim 8 wherein the buffer is a mixture of citric acid and sodium citrate in a ratio of about 70:30 to about 82: 18 by weight.

12. The chloral hydrate solution of claim 3 wherein the one or more pharmaceutically acceptable excipients include a pH adjusting agent.

13. The chloral hydrate solution of claim 12 wherein the pH adjusting agent is selected from hydrochloric acid, a water soluble organic acid and mixtures thereof.

14. The chloral hydrate solution of any one of claims 3 to 13 wherein the diluent is selected from water, alcohol, liquid glucose, syrup, sorbitol, glycerol, propylene glycol, polyethylene glycol and mixtures thereof.

15. The chloral hydrate solution of any one of claims 3 to 14 wherein the sweetener is selected from agave nectar, brown rice syrup, hydrogenated glucose syrup, date sugar, honey, molasses, blackstrap molasses, sorghum syrup, stevia, maple syrup, birch syrup, yacon syrup, lucuma powder, coconut sugar, erythritol, maltitol, mannitol, sorbitol, xylitol, isomalt crystals, lactitol, maltitol, acesulfame, advantame, alitame, allulose, aspartame, neotame, saccharin, sodium saccharin, sucralose, acesulfame potassium, tagatose, thaumatin, stevioside and mixtures thereof.

16. The chloral hydrate solution of any one of claims 3 to 15 wherein the flavouring agent is selected from almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, mango, grape, grapefruit, guava, hop, lemon, licorice, lime, elderberry, malt, mandarin, molasses, nutmeg, mixed berry, orange, peach, pear, peppermint, pomegranate, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla, winter green, tutti-frutti, bubblegum and mixtures thereof.

17. The chloral hydrate solution of any one of claims 3 to 16 wherein the antimicrobial agent is selected from benzoic acid, methyl paraben, propyl paraben, butyl paraben, sorbic acid and their pharmaceutically acceptable salts, and mixtures thereof.

18. The chloral hydrate solution of any one of claims 1 to 17 wherein the solution has no more than 300 ppm of chloroform, no more than 800 ppm of formic acid and no more than 100 ppm of monochloroacetaldehyde at the end of 24 months when stored below 25 °C.

19. The chloral hydrate solution of any one of claims 1 to 18 wherein the chloral hydrate is present in an amount of about 500mg/5ml.

20. The chloral hydrate solution of any one of claims 1 to 18 wherein the chloral hydrate is present in an amount of about 143mg/5ml.

21. The chloral hydrate solution of any one of claims 1 to 20 for use in a method of treatment of the human or animal body.

22. The chloral hydrate solution of any one of claims 1 to 20 for use in the treatment of insomnia.

23. The chloral hydrate solution of any one of claims 1 to 20 for use in a method of sedating a subject.

24. The chloral hydrate solution for use according to any one of claims 21 to 23, wherein the chloral hydrate solution is administered orally.

25. A method of preparing the chloral hydrate solution of any one of claims 1 to 20, comprising mixing the chloral hydrate with the one or more pharmaceutically acceptable excipients in an aqueous solution.