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Hydromorphone

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The name of the drug is called Hydromorphone. The systematic name (IUPAC) is 4,5-epoxy-3-hydroxy-17-methylmor-phinan-6-one.

Hydromorphone has a chemical formula of C17H19NO3 . There are four functional groups in Hydromorphone:

  1. An Ether group
  2. A Ketone group
  3. An Amine group (tertiary)
  4. A Phenol group

Stereochemistry and conformation:

Hydromorphone has 4 chiral centres (Four different groups attached to a sp3 hybridised carbon - one chiral centre). Therefore it has 24 = 16 stereoisomers.

Carbon number 1 has R-configuration

Carbon number 2 has R-configuration

Carbon number 3 has S-configuration

Carbon number 4 has R-configuration

Hydromorphone is a semi-rigid molecule because it is composed of a five-member ring system: the phenolic ring (A), the cyclohexane ring (B), the cyclohexanone ring (C), the N-methyl piperidine ring (D), and the tetrahydrofuran ring (E). The molecule has a "T" shape. Rings A, B and E form a vertical plane where the C and D form the horizontal plane. Ring C exists in a chair conformation due to saturation of C-C double between C7 and 8. Ring D also exists in chair conformation.

Synthesis:

Commercially, Hydromorphone is made from morphine via either direct rearrangement (reflux alcoholic or acidic aqueous solution of morphine with platinum or palladium catalyst) or reduction of morphine via catalytic hydrogenation, this two reactions both produce Dihydromorphine. The Dihydromorphine then undergo Oppenauer oxidation, where it is oxidised with benzophenone in the presence of potassium tert butoxide or aluminium tert butoxide to form Hydromorphone.

Drug stability:

The half-life of Hydromorphone is 2.6hours through oral route, where it takes 18.6 hours for sustained release Palladone. Hydromorphone hydrochloride is affected by light, although hydromorphone hydrochloride injection may develop a slight yellowish discoloration, this change does not indicate loss of potency. Hydromorphone hydrochloride injection should be protected from light and stored at a controlled room temperature of 25 degrees C, but can be exposed to temperatures ranging from 15 to30 degrees C; freezing of the injection should be avoided. Hydromorphone hydrochloride tablets should be stored in tight, light-resistant containers, usually at 15 to30 degrees C; however, the manufacturer recommends that the 8-mg tablets be stored at 15 to 25 degrees C. Hydromorphone hydrochloride oral solution should be stored in light-resistant containers at 15 to 25 degrees C, and suppositories of the drug should be stored at 2 to 8 degrees C.

Hydromorphone hydrochloride injection reportedly is physically and chemically stable for at least 24 hours in most common IV infusion solutions when protected from light at 25 degrees C. Hydromorphone is slightly soluble in water, freely soluble in alcohol and very soluble in chloroform.

Formulation and packaging:

In the U.K. Hydromorphone is only available in form of oral capsules and modified release capsules, which means it is released slowly to extend the length of the drug's effect.

Available strengths for hydromorphone hydrochloride (Palladone®): 1.3mg (orange/clear), net price 56-capsules pack = £8.82; 2.6mg (red/clear), 56- capsules pack = £17.64.

Where for the modified (release Palladone® SR): m/r, hydromorphone hydrochloride 2mg (yellow/clear), net price 56- capsules pack = £20.98; 4mg (pale blue/clear), 56- capsules pack = £28.75; 8mg (pink/clear), 56- capsules pack = £56.08; 16mg (brown/clear), 56- capsules pack = £106.53; 24mg (dark blue/clear), 56-cap pack = £159.82. [BNF 56 page 235-236].

Lipinski's Rules:

  • The molecular weight of Hydromorphone is 285 g/mol. (below 500)
  • The Log P of Hydromorphone is +1.69. (lower than +5)
  • There is only one hydrogen bond donating group, which is the hydroxyl group in Phenol. (less than 5 groups)
  • here are only three hydrogen bond accepting groups. (less than 10 groups)
  • The functional groups are generally stable to metabolism, i.e. hydrolysis and oxidations.

According to the Lipinski's rules of 'five', Hydromorphone is an orally active drug.

LogP and discussion of hydrophobic/hydrophilic properties:

It is possible to predict the Log P of a molecule by using the Hydrophilic-Lipophilic Values (p Values) for organic fragments.

This gives (+0.5 x 11) + (+2 x 1) + (-1 X 3) + (-1 X1) = +3.5. Therefore, the Predicted LogP = +3.5. Since 3.5 is greater than 0.5, hydromorphone is insoluble in water. (Soluble in water if smaller than 0.5)

According to the predicted LogP, Hydromorphone is a very hydrophobic (lipophilic) drug and it can pass through the membrane layers in cell and enter the bloodstream (high absorption). Hydromorphone is insoluble in water because of its non-polar groups. They are: The long aliphatic and aromatic hydrocarbons, i.e. cyclohexanes and the phenyl group. These non-polar groups will not interact with polar water molecules as they cannot form hydrogen bonds together and therefore insoluble.

pKa and ionisation state:

Hydromorphone has a pKa of 8.2 at 20 degrees C [Medicine Complete], it is weakly acidic.

To calculate the percentage of ionization of Hydromorphone (weak acid) at different pH, Equation 1 can be used:

Equation 1 - % ionisation= 1001+antilog(pKa-pH)

At pH 2: % ionization

= 1001+antilog(8.2-2)

= 6.31 x 10-5 %

At pH 7.4: % ionization

= 1001+antilog(8.2-7.4)

= 13.7%

At pH 10: % ionization

= 1001+antilog(8.2-10)

= 98.4%

From the calculations on the previous page, I can conclude that only 6.31 x 10-5 % of hydromorphone is ionized at pH 2, i.e. in the stomach. Therefore, there are 100% - 6.31 x 10-5 % = 99.9999% of unionised Hydromorphone which can pass through the membrane barrier and enter the bloodstream. Hydromorphone is highly absorbed by the body in stomach.

Mode of action:

Hydromorphone is an opioid analgesic; it reacts with the opioid mu-receptors. The mu-receptors are discretely distributed in the human brain with high density in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and certain cortical areas. These receptors are also found in the spinal cord and gastrointestinal tract. It binds onto the mu-receptors and exerts its principle pharmacological effect on the Central Nervous System and gastrointestinal tract to produce analgesia and sedation. Hydromorphone is highly absorbed by the human body and it shows the analgesia effect very quickly once enter the body. It is 8 to 10 times stronger than morphine due to its hydrophobicity (very lipophilic).

Bibliography:

  1. Samuel, B., Stanley,G., Robert, R. (2004), Process for the Synthesis of Hydromorphone, http://www.wipo.int/pctdb/en/wo.jsp?WO=2006005112&IA=AU2005001002&DISPLAY=DESC, Date accessed 23/04/10.
  2. Author unknown. (Date unknown), One-pot Isomerization of Morphine to Dihydromorphinone (Hydromorphone), http://www.erowid.org/archive/rhodium/chemistry/dihydromorphinones.html, Date accessed 23/04/10.
  3. Author unknown.(2006), Hydromorphone, http://www.patient.co.uk/medicine/Hydromorphone.htm, Date accessed 23/04/10.
  4. Hildebrand, K., Elsberry, D., Anderson, V. (2001), 'Stability and Compatibility of Hydromorphone Hydrochloride in an Implantable Infusion System', Journal of Pain and Symptom Management, 22 (6), Page 1042-1047.
  5. Author unknown. (2010), Hydromorphone Suppository, http://www.drugs.com/cdi/hydromorphone-suppository.html, Date accessed 24/04/10
  6. Lipinski, C. (2004), Lipinski's rule-of-five, http://www.bioscreening.com/reference/lipinski_rule.htm, Date accessed 24/04/10.
  7. Author unknown. (2009), Showing drug card for Hydromorphone (DB00327), http://www.drugbank.ca/drugs/DB00327, Date accessed 24/04/10.
  8. Clarkes. (2006), Clarke's Analysis of Drugs and Poisons - Hydromorphone, http://www.medicinescomplete.com/mc/clarke/2009/CLK0851.htm, Date accessed 24/04/10.
  9. Author unknown. (2008), Monograph - Hydromorphone Hydrochloride, http://www.medscape.com/druginfo/monograph?cid=med&drugid=11338&drugname=Hydromorphone+Rect&monotype=monograph&print=1, Date accessed 24/04/10.
  10. BMJ Group,. (2008). British National Formulary 56, London, RPS Publishing.
  11. Bruice, P,. (2004). Organic Chemistry, Fourth Edition,Prentice Hall ,Pearson.
  12. Lo,K,. (1998) Synthesis of N- Phenethylnorhydromorphone, https://circle.ubc.ca/bitstream/handle/2429/11862/ubc_2001-0456.pdf;jsessionid=8D12F28D380E801AE9A422C0F9CD3435?sequence=1, Date accessed 26/04/10

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