Oral physico-chemical properties

An important part of the optimization process of potential leads to candidates suitable for clinical trials is the detailed study of the absorption, distribution, metabolism and excretion (ADME) characteristics of the most promising compounds. Experience has learned that physico-chemical properties play a key role in drug metabolism and pharmacokinetics (DMPK) [1-3]. As an example, physicochemical properties relevant to oral absorption are described in Fig. 1.1. It is important to note that these properties are not independent, but closely related to each other. 

Fig. 1.1. Relationships between various physico-chemical properties believed to influence oral drug absorption.

In addition, the calculation of many different ID, 2D and 3D descriptors is possible using a range of commercially available software packages, such as Sybyl, Cerius2, Tsar, Molconn-Z and Hybot. Several new descriptor sets are based on quantification of 3D molecular surface properties, and these have been explored for the prediction of, e.g., Caco-2 permeability and oral absorption. It is pointed out here that a number of these new descriptors are strongly correlated to the more traditional physico-chemical properties. 

Until recently, nonparenteral routes have failed to deliver sufficient quantities of ASO to be systemically therapeutic. The recent advent of novel oral delivery technologies, coupled with the increased tissue residence time for second-generation ASOs, allows oral delivery to achieve therapeutic levels for select systemic indications. This chapter will initially outline certain more conventional aspects of parenteral dosage forms, and then focus on formulation technologies that more specifically address local treatment. For the oral route, we will pass to the biopharmaceutic considerations for both local delivery to the gut and systemic delivery via absorption from solid dosage forms. Incumbent with the discussion on formulations is the need initially to overview the physico-chemical properties of ASOs, which in large part determine their biopharmaceutic characteristics. 

From the above described antitumor and emesis studies, JM216 was selected on the basis of possessing both good oral antitumor activity against a variety of murine and human ovarian tumor models, a low emesis score in the ferret and favourable physico-chemical properties. 

The failure of drugs at later stages of development, particularly in clinical trials, is very expensive for drug developers and, more importantly, patients. To better understand the key reasons for these failures, Lipinski et al,14 undertook an analysis of the properties of compounds that entered Phase II human clinical trials. They selected a subset of 2245 compounds from the World Drug Index (WDI) database of over 50000 compounds after eliminating the majority of compounds for various well-reasoned criteria. This subset of compounds had assigned trade names and, as a result, were assumed to have entered Phase II oral efficacy studies and be expected to have superior physico-chemical properties since they would have passed most of the other earlier clinical trial hurdles. 

An oral ADME (absorption, distribution, metabolism, excretion, following oral administration of the pesticide) study may also be of utility in refining the risk assessment. If a default value for dermal absorption of 100 % is applicable based on the physico-chemical properties of a substance and an appropriate oral ADME study is available, the results of this study may be used to refine the default value for dermal absorption. It is required that the oral absorption is determined at low dose levels in experimental animals, in order to obtain an accurate estimate of the oral absorption. Based on theoretical grounds and supported by a comparison of oral and dermal absorption data available for twelve pesticides, it is assumed that dermal absorption will not exceed oral absorption (Hakkert et al unpublished data). 

Amoxicillin is well absorbed when given orally, with a bioavailability that appears to be much higher than expected in the light of its physico-chemical properties and the pH partition theory [191], Numerous studies show recovery of intact amoxicillin in urine after oral administration in the range 43 to 80 % after 6 to 8 hours, with most figures in the upper part of this range [147,171,172,187,188,190]. An additional 10 to 25 % of the dose appears in urine as the penicilloic acid [147,148,152,171,172,187] with a ratio of about 2 to 1 of the 5R to 5S isomers [152,171,172]. Amoxicillin is extensively distributed in body tissues and fluids, with adequate levels for antibacterial activity in most of them [187,188,190], The half life in serum is about one hour and is the same for oral, intramuscular and intravenous administration [187,188,190]. Co-administration with potassium clavulanate does not affect the absorption, distribution and excretion of amoxicillin [190]. 

The filter of Wenlock et al. is derived from a statistical analysis of a set of marketed oral drugs that are compounds with acceptable physico-chemical properties that have successfully enabled them to overcome the obstacles of development for their desired therapeutic indication. 

Exposure is assessed from the use pattern, quantity to be sui lied and physico-chemical properties. A substance is considered hazardous to health if the rodent oral LD50 <300 mg kg or it is suspected of being mutagenic or carcinogenic. A substance is considered to be hazardous to the environment either if it is not biodegradable and the abiotic degradation data and physico-chemical properties indicate it will remain in the environment, or if the information on ecotoxicity and bioaccumulation suggest special control measures are needed. 

PCA test and more potent than the acrylic acid (4a). The physico-chemical properties of 5a differed from those of the acid ( ). The intramolecular hydrogen bonding between the carbonyl and tetrazole groups was not observed in 5a which showed a stronger acidity (pKa 5-85 in dimethyl sulfoxide-H20 or pKa 4.3) than the corresponding 3a and also the acrylic acid (4a). Hence, an extensive study on the synthesis and the structure-activity relationships of this orally effective series of tetrazolylchromones 5 was conducted (22 ). ... 

Martins, S. Sarmento, B. Souto, E.B. Ferreira, D.C. Insulin-loaded alginate microspheres for oral delivery—Effect of polysachharide reinforcement on physico-chemical properties and release profile. Carbohydr. Polym. 2007, 69 (4), 725-731. 

The pharmacist should have anticipated the bio-pharmaceutical consequences of the physico-chemical properties of oxcarbazepine. The drug is classified as a Class II substance for oral application. Logically, lack of adequate solubility is even more evident for the rectal administration as the volume of rectal fluid is limited (see Table 17.1). With an aqueous solubility of approximately 300 mg/L, the solubUity of the substance in the lipophilic base of the suppositories would certainly not be higher than 9.5 mg/mL (being a direct consequence of the value of the log P = 1.5 of oxcarbamazepine). This means that oxcarbazepine is not dissolved in the lipid but dispersed as crystals, which settle from the molten suppository once introduced in the rectal cavity. The amount of rectal liquid is limited and therefore a saturated solution will exist which involves only less than 1 mg dissolved oxcarbamazepine. Low solubility yields a low concentration and hence a low driving force for diffusion to occur. As a consequence, the rate of absorption is relatively low. This slow release may lead to hardly any uptake, due to defecation within several hours after insertion. 

The leaching potential from polymers is unknown, but is expected to be low in view of its very low water solubility and strong adsorption to organic carbon. Similarly, the low vapor pressure should limit its volatility. Emissions from landfills are therefore expected to be relatively small. This substance is poOTly absorbed via the oral route. Based on physico-chemical properties, absorption following inhalation or dermal exposure is likely to be very low. 

Properties Almost wh. gran. dens. 0.94-0.96 g/cm (23 C) vise. = 350 mPa s (120 C) drop pt. 103-108 C acid no. 15-19 Toxicology LD50 (oral, rat) > 2000 mg/kg Environmental Biodeg. > 95% physico-chemically eliminable Storage 2 yrs min. shelf life when stored in dry area normal ambient temps. 

Transfer of an active substance across a biological membrane is influenced by different physico-chemical drug properties, which are combined in Lipinski s ([7] Rule-of-5 . This rule predicts poor absorption of an orally administered active substance when it ... 

Low BS, Teh CH, Yuen KH, Chan KL (2011) Physico-chemical effects of the major quassinoids in a standardized Eurycoma longifolia extract (Fr 2) on the bioavailability and pharmacokinetic properties, and their implications for oral antimalarial activity. Nat Prod Commun 6 337-341... 

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