Morphine ionization

At pH 9.05, the phenol-phenolate equilibrium favours the phenol by a factor of 7 1, and the amine-ammonium ion equilibrium favours the amine by a factor of 7 1. In other words, the non-ionized morphine predominates, and this can thus be extracted into the organic phase. What about the amounts in ionized form are these not extractable By solvent extraction of the non-ionized morphine, we shall set up a new equilibrium in the aqueous phase, so that more non-ionized morphine is produced at the expense of the two ionized forms. A second solvent extraction will remove this, and we shall effectively recover almost all the morphine content. A third extraction would make certain that only traces of morphine were left as ionized forms. 

In the BBB-PAMPA lipid formulation illustrated in Fig. 3.4, the diff values, defined as the difference log Pq-log Pi, range from 2.9 (morphine) to 4.2 (warfarin), somewhat similar to the values observed in the octanol-water system. However, it is premature to propose a pdiffi-A approximation, given the limited amount of data reported. With other lipid formulations, larger differences are usually observed. In Double-Sink PAM PA, and especially in hexadecane-PAMPA, transport of ionized drugs has not been reported [84]. 

Fig. 2.1. Lipophilicity profiles for diclofenac (acid), propranolol (base) and morphine (ampholyte). Dashed lines indicate the pH range where molecule may partition in its ionized form.

Opioid levels in the brain are significant within seconds to minutes after injection. As mentioned before, heroin is more lipid soluble than morphine, so a greater amount penetrates the brain. Lipid solubility and ionization are the predominant factors that determine the distribution of opioids (Mather 1987). At therapeutic concentrations, about one-third of morphine is bound to protein in the blood. 

Bogusz MJ, Maier RD, Erkens M, Driessen S. 1997. Determination of morphine and its 3- and 6-glucuronides, codeine, codeine-glucuronide and 6-monoacetylmorphine in body fluids by liquid chromatography atmospheric pressure chemical ionization mass spectrometry. J Chromatogr B Biomed Sci Appl 703 115. 

The optimum pH will be the isoelectric point as described under amino acids (see Section 4.11.3). This is the pH at which the concentrations of cationic and anionic forms of morphine are equal, and is the mean of the two p a values. Morphine has pATa (phenol) 9.9, and pATa (amine) 8.2, so that pi = 9.05. Note that the protonated amine is a stronger acid than the phenol, so that the intermediate between the two ionized forms will be the non-ionized alkaloid. 

Here k f k2f and kare microscopic ionization constants defined in section 4.6. From this it was possible to calculate and plot variation in Dnoh with pH for pentazocine as shown in Figure 2. The fourth partition coefficient was obtained by structural group contribution to the measured partition coefficient of a reference compound (morphine). This was done following the Hansch approach. 

Edder et al. reported the capillary supercritical fluid chromatography of basic drugs of abuse, namely nicotine, caffeine, methadone, cocaine, imipramine, codeine, diazepam, morphine, benzoylecgonine, papverine, narcotine, and strychnine [25]. They compared the separation of these drugs on DBS and DB wax columns. The chromatographic conditions included a carbon dioxide mobile phase and a flame-ionization detector. It was noted that on the DBS column, all peaks other than methadone and cocaine were separated. With the exception of benzoylecgonine and papaverine, all other peaks were separated on a DB wax column. A reproducibility of less than 5% was obtained with an internal standard method. The detection limits obtained were within 10-50 ppm on both the columns. A linearity of >0.99 was obtained for methadone, codeine, and morphine in the concentration range 10-1000 ppm. 

R. Saferstein, J. Manura, and T. A. Brettell, Chemical ionization mass spectrometry of morphine derivatives, J. Forens. Sci., 24 312... 

Huang DK, Liu C, Huang MK, Chien CS (2009) Simultaneous determination of morphine, codeine, 6-acetylmorphine, cocaine and benzoylecgonine in hair by liquid chromatography/ electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom 23(7) 957-962. doi 10.1002/rcm.3955... 

Other definitive metabolites which are used in our laboratory as indicators of drug use are cocaethylene, norcocaine, A9-carboxy-tetrahydrocaimabinol (carboxy-THC) (a substance which is not found in smoke from a marijuana cigarette), and the heroin metabolites 6-MAM and morphine glucuronide. Drugs and metabolites are measured by ultrasensitive GC/MS/MS or chemical ionization ion-trap GC/MS techniques requiring 5 mg or less of sample. ... 

N-C Hj-morphine as internal standard. The internal standard was added to 10 ml urine, the urine buffered to pH 8.5 and extracted with chloroform isopropanol (4 1). The extraction residue was trimethylsilylated by adding 25 ul of N,0-bis(trimethylsilylJacetamide and heating at 60°C for about 1 h. About 2 ul was analyzed on a 3 % 0V-17 column at 230°C coupled direct to a Finnegan 1015 quadrupole mass spectrometer equipped with a chemical ionization source, which was operated at an ionizing energy of 100 eV, an ion repeller voltage of 0 V and a filament emission of 300 uA. The mass spectrometer was interfaced with a System Indus-... 

HPLC-MS and CE-MS with atmospheric pressure ionization in analyses of morphine and related compounds 04CL336. 

Much of the beneht in solubihty enhancement from salt formation is attributable to the change in solution pH caused by the presence of the counterion. This occurs because the ionization and solubility of acidic drugs (such as barbiturates and non-steroidal anti-inflammatory drugs) increases in basic conditions but decreases in acidic conditions. This behavior is exemplified by derivations of the Henderson-Hasselbalch equations (37.2) and (37.3). The opposite situation occurs for basic drugs such as chlorpromazine, morphine and codeine, which are more soluble in acidic conditions. 

Example Morphine is a weak base (pKa 8.0). What percentage will be in the ionized form in the urine at a pH of 6.0 ... 

From Table 1-1-1,1% of morphine is in the nonionized form thus, 99% is ionized. 

Leis HJ, Fauler G, Raspotnig G, Windischhofer W. Quantitative analysis of morphine in human plasma by gas chromatography-negative ion chemical ionization mass spectrometry. J Chromatogr B 2000 744 113-9. 

Substitution of tetrazol-5-one for the thiophene ring in sufentanil results in a decrease in potency ( 25 times that of morphine) and a decrease in the pKa of the resultant compound, alfentanil (Table 24.4). The lower pKa of alfentanil results in a lower percentage of the drug existing in the ionized form at physiological pH. Being more un-ionized, alfentanil penetrates the blood-brain barrier faster than other fentanyl derivatives and has a faster onset and shorter duration of action. Alfentanil is 99% metabolized in the liver and has a half-life of only 1.3 hours. Alfentanil is available as an intravenous dosage form for use in ultrashort anesthetic procedures. 

Dissociation constants and corresponding pK values of the drugs were obtained from measured free-base solubilities (determined at high pH s) and the concentrations of saturated solutions at intermediate pH s. Morphine, fentanyl, and sufentanil exhibited pJCa values of 8.08,8.99, and 8.51, respectively. Over the pH range of 5 to 12.5 the apparent solubilities are determined by the intrinsic solubility of the free base plus the concentration of ionized drug necessary to satisfy the dissociation equilibrium at a given pH."... 

Molecular absorbance with ionization (dA/dpH method), 12 Morphine, 3... 

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