Abstract
A drug delivery system (DDS) is defined as a formulation or a device that enables a therapeutic
substance to selectively reach its site of action without reaching the nontarget cells, organs, or
tissues. It can also be understood as an approach associated with transporting a pharmaceutical
compound to its target site to accomplish a desired therapeutic effect. The drug delivery process
is affected by many factors and parameters including temperature, pH, the drug itself, the
composition, particle size and the partitioning coefficient among many more.1 This literature
survey aims to develop an understanding about the broad topic of drug delivery focusing mainly
on the effect of the partitioning coefficient and the particle size on the drug delivery process.
Moreover, it will highlight how the partitioning coefficient and particle size of a particular drug
play a role in the drug release and absorption through membranes in the human body.
1
Chackalamannil,S, Rotella, D, Ward, S.(2017) Comprehensive Medicinal Chemistry III. Available at:
https://www.sciencedirect.com/referencework/9780128032015/comprehensive-medicinal-chemistry-iii (Downloaded: 9 April
2023)
Introduction
Drug delivery refers to techniques for introducing and distributing medications or drugs inside the
body. The process of drug delivery involves numerous molecular pathways, and for a drug to have
therapeutic effects in a living organism, it must be efficiently and accurately transported to the
target region, absorbed and released without interfering with other cells. This process is tedious
and various drug administration routes are established to increase the target efficiency and reduce
the biological barriers, such as mucus barrier, blood brain barrier and cell membrane barrier.2 One
of the many biological barriers that are faced in the drug delivery process are the cell membranes.
The ability of the drug to cross or permeate the cell membranes is one of the most important steps
in the process. To begin with, a drug can be classified as hydrophilic or lipophilic. This depends
on their ability to dissolve in water or in lipid-containing media. In this respect, absorption is faster
in lipophilic drugs as lipophilic compounds tend to have a greater affinity for metabolic enzymes
which leads to not only greater metabolic clearances and absorption but also contributes to higher
permeability in membranes.3 This plays a significant role in drug delivery as membrane
penetration and other partitions are controlled by a number of physico-chemical parameters, the
most prominent include lipophilicity. Drug delivery is a cascade of molecular migration processes,
in which the active ingredient dissolves in and partitions between several biological media of
various hydrophilic and lipophilic character.
The partitioning coefficient is the measure of the lipophilicity of a drug and an indication of its
ability to cross the cell membrane. It is defined as the ratio between un-ionized drugs distributed
between the organic and aqueous layers at equilibrium. It can also be understood as the partition
of a neutral uncharged species into the oil or water phase. The partitioning coefficient measures
how hydrophobic or hydrophilic a chemical substance is. Drugs with high partition-coefficient
value can easily permeate through biological membranes, due to their lipophilic nature. The speed
at which drug molecules diffuse into matrix systems or through rate-controlling membranes is
primarily determined by the partition coefficient.4
The determination of the partitioning coefficient of a drug can be done experimentally by using
various methods5. The most common method is the shake-flask method, in which the drug is placed
2
K.S. Yadav, D.C. Dalal. (15 June 2021) The heterogeneous multiscale method to study particle size and partitioning effects in
drug delivery. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0898122121001000
(Accessed: 9 April 2023)
3 Climent, E, Benaiges, D, Pedro-Botet, J. (20 May 2021) Hydrophilic or Lipophilic Statins? Available at:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172607/#:~:text=The%20classification%20of%20drugs%20as,is%20greater%2
0in%20hydrophilic%20medications
(Accessed: 9 April 2023)
4
Grumezescu, A.M. (2018) Drug Targeting and Stimuli Sensitive Drug Delivery Systems. Available at:
https://www.sciencedirect.com/book/9780128136898/drug-targeting-and-stimuli-sensitive-drug-delivery-systems
(Downloaded: 9 April 2023)
5 Mallikarjuna Rao, Kishore Kumar, M., & Malla Reddy, C. (2011). A review on partition coefficient and its determination methods.
Der Pharmacia Lettre, 3(2), 267-276.
1
in a mixture of the two solvents (water and octanol) and shaken vigorously to allow the drug to
distribute itself between the two phases until equilibrium is reached. The partitioning coefficient
is defined as the ratio of the drug concentration in the organic phase (octanol) to that in the aqueous
phase (water) when the two phases are in equilibrium. So, after equilibrium is reached the
concentrations of the drug in each phase are then determined, usually by analytical techniques such
as UV spectrophotometry, and the partitioning coefficient is calculated as the ratio of the
concentration in the octanol phase to that in the aqueous phase6. It is important to note that the
partitioning coefficient can vary depending on several factors such as temperature, pH, and the
presence of other solutes in the system. Therefore, it is important to standardize the conditions
under which the partitioning coefficient is measured.
Particle size analysis is an important parameter in drug delivery systems as it can affect the drug's
solubility, stability, and bioavailability. There are several methods for determining the particle size
of drugs in drug delivery systems, including microscopy, laser diffraction, dynamic light
scattering, and sedimentation analysis7. Microscopy methods involve the use of optical or electron
microscopy to observe and measure the size and shape of particles. Laser diffraction methods use
a laser beam to scatter light off the particles and determine their size based on the diffraction
pattern. Dynamic light scattering measures the size of particles by analyzing the fluctuations in
scattered light caused by Brownian motion. Sedimentation analysis involves the measurement of
the rate at which particles settle in a liquid medium, which is related to their size. At the end, each
method has its advantages and limitations, and the choice of method depends on the nature of the
drug delivery system and the specific requirements of the study.
6
Huang, Y., Li, X., Li, Y., Li, H., & Li, G. (2018). Determination of the octanol/water partition coefficient (logP) of triclosan by
HPLC. Journal of Chemistry, 2018, 1-6.
7 Bhushan, B., & Prajapati, R. (2017). Particle size analysis in pharmaceutical manufacturing process. Journal of Pharmaceutical
Research and Clinical Practice, 1(1),
2
Discussion
It is significant to note that drugs are absorbed by passive diffusion across a lipophilic cell
membrane into the blood in order to be transported to its target site. Therefore, lipophilicity is an
important property of a drug that influences this process and the partitioning coefficients are very
useful in determining and estimating the distribution of drug molecules within the body as it gives
a measure of a solute’s hydrophobicity and a representation for its ability to permeate a membrane.
Another parameter that must be taken into consideration in the drug delivery process is the particle
size. Particle size is a key parameter for drug delivery. It is believed that the size of a particle may
have important effects on its ability to overcome the transport barriers in biological tissues.
Theoretically, to overcome the biological barriers and allow the drug to reach its target site, the
molecules must possess a specific size.8
The particle size of a drug can affect the drug delivery process where it determines the rate and
extent of drug absorption and influences the drug's bioavailability which refers to the fraction of
the administered dose that reaches the systemic circulation and is available for the desired
pharmacological effect. After the investigation of several scientists, it was found that the effect of
particle size on the dissolution rate of multiple drugs, mostly water-poor drugs that are soluble,
such as, griseofulvin, phenylbutazone, and indomethacin is majorly significant. Reducing the
drug's particle size will lead to an increase in the surface area, which results in faster drug
absorption and higher bioavailability9 that’s because smaller particles are more easily dissolved in
water, leading to a higher concentration of drug molecules that come into contact with the
dissolution medium which are available for absorption, as well as a significant increase in the
dissolution of the drug that enhances the release rate of drug delivery due to increased surface area
and improved wettability, which leads to faster drug diffusion or erosion of the delivery system.
Nonetheless, particle size can also impact the stability of drug molecules10 because smaller
particles are more prone to aggregation or degradation, which results in a reduced stability of the
drug during storage or in general physiological conditions, also noting that these small particles
may have different interactions with biological tissues or cells compared to larger particles, which
can possibly affect their biocompatibility, toxicity, or immunogenicity11.
8
Islam, M.A., Barua, S. & Barua, D. A. (25 November 2017). Multiscale modeling study of particle size effects on the tissue
penetration efficacy of drug-delivery nanoparticles. Available at: https://bmcsystbiol.biomedcentral.com/articles/10.1186/s12918017-0491-4#citeas
(Accessed: 9 April 2023)
9 Chingunpituk J. Particle size effect on the solubility and bioavailability of poorly soluble drugs: theory and practice. Eur J Pharm
Sci. 2016 Feb 15;89:181-94. doi: 10.1016/j.ejps.2016.04.014. Epub 2016 Apr 16. PMID: 27091283.
10 Gao L, Zhang D, Chen M. Drug nanocrystals for the formulation of poorly soluble drugs and its application as a potential drug
delivery system. J Nanopart Res. 2008;10(5):845-62. doi: 10.1007/s11051-007-9309-9. Epub 2008 Jan 29. PMID: 18769649;
PMCID: PMC2564352.
11 Nel A, Xia T, Mädler L, Li N. Toxic potential of materials at the nanolevel. Science. 2006 Jan 20;311(5761):622-7. doi:
10.1126/science.1114397. PMID: 16456071.
3
Several studies were conducted to prove the effect of particle size on drug delivery. For instance,
a study conducted by Wang in 2018 investigated the effect of particle size on the bioavailability
of geniposide, which is a natural product with therapeutic potential for inflammatory diseases. The
researchers prepared geniposide nanoparticles with particle sizes (ranging from 80 nm to 560 nm)
and evaluated their pharmacokinetic profiles in rats. The results obtained confirmed that the
smaller nanoparticles (80 nm and 220 nm) exhibited significantly higher bioavailability compared
to the larger nanoparticles (340 nm and 560 nm) which leads to the conclusion that reducing
particle size can enhance the oral bioavailability of geniposide and improve its therapeutic
efficacy. Another study was conducted by Xu in 2018 that investigated the effect of particle size
on the bioavailability of quercetin in rats where the results also showed that smaller particles of
quercetin had higher bioavailability compared to larger particles. Similarly, a study by Abdelbary
in 2012 found that the bioavailability of tadalafil increased when the particle size was reduced12.
In addition, the particle size of drugs plays an important role in determining their ability to cross
the blood-brain barrier (BBB) and penetrate into the brain tissue. The BBB is a highly specialized
system of tightly-packed cells that line the blood vessels in the brain and prevent the free exchange
of molecules between the bloodstream and the brain tissue.13 Although the BBB is critical for brain
function, it can also pose a challenge for drug delivery to the brain, as many drugs are unable to
cross the barrier. As a result, there is significant interest in developing strategies to bypass or
overcome the BBB for the treatment of neurological disorders and brain tumors. Generally,
particles with a diameter less than 100 nm are believed to have a better chance of crossing the BBB
and have shown promising results in enhancing brain drug delivery 14. Nanoparticle-based drug
delivery systems have been extensively studied as a means of enhancing brain drug delivery by
taking advantage of their small size and surface properties. Various types of nanoparticles,
including liposomes, solid lipid nanoparticles, and polymeric nanoparticles, have been
investigated for their ability to cross the BBB15. The size and surface properties of these
nanoparticles can be carefully controlled and tailored to enhance their ability to cross the BBB16.
Another parameter affecting the drug delivery process is the partitioning coefficient, which
describes the partitioning of a drug between two immiscible phases, typically a hydrophobic and
a hydrophilic phase. In drug delivery, several factors can influence the effect of partitioning
coefficient on drug delivery as it is highly influenced by the solubility of the drug in the respective
phases where drugs with higher solubility in the hydrophobic phase, higher partitioning
12
Abdelbary, G. A., El-Gendy, N. A., & Youssef, A. M. (2012). Nanoparticles for enhancement of oral bioavailability of tadalafil:
preparation and in vitro and in vivo evaluation. International Journal of Nanomedicine, 7, 3027–3038.
13 Abbott, N. J., Patabendige, A. A., Dolman, D. E., Yusof, S. R., & Begley, D. J. (2010). Structure and function of the blood-brain
barrier. Neurobiology of Disease, 37(1), 13-25.
14 Huile, G., Shu, C., & Jiang, Q. (2016). The blood-brain barrier (BBB) permeability in Alzheimer's disease (AD) and the delivery
of drugs to the brain. Asian Journal of Pharmaceutical Sciences, 11(3), 303-312.
15 Kuo, Y. C., Lin, C. H., & Chen, C. C. (2017). Evaluation of blood-brain barrier permeability using in vivo perfusion techniques:
Quantitative analysis and determination of cutoff size. BioMed Research International, 2017, 1-9.
16 Chen, X., Chen, Y., Wu, J., Li, Y., Hu, H., Liu, Y., ... & Li, W. (2018). Preparation of brain-targeting rivastigmine-loaded solid
lipid nanoparticles by co-grinding and ultrasonication method. Colloids and Surfaces B: Biointerfaces, 162, 305-311.
4
coefficient, are more likely to accumulate in lipid-based delivery systems, such as liposomes,
micelles, or lipid nanoparticles. However, drugs with higher solubility in the hydrophilic phase,
lower partitioning coefficient, are more likely to be distributed in aqueous-based delivery systems,
such as emulsions or hydrogels17. The coefficient can also affect the drug loading capacity of drug
delivery systems18. A possibility of allowance in higher drug loading in hydrophobic-based
delivery systems is due to a higher partitioning coefficient, where the drug molecules can be
incorporated into the lipid or hydrophobic core of the system. In contrast, lower partitioning
coefficients may limit drug loading where the drug molecules may be dispersed in the aqueous
phase. However, it’s also a reason for the influence of the rate at which a drug is released from a
delivery system, where higher partitioning coefficients tend to have slower release rates from
hydrophobic-based delivery systems because of their strong affinity to the lipid phase that leads to
a more sustained and controlled drug release which conversely means that faster release rates from
hydrophilic-based delivery systems are ought to happen due to their weaker affinity to the aqueous
phase at a lower partitioning coefficient. Another important factor is the stability of the drug where
drugs that may be more prone to chemical degradation or physical instability in hydrophobic-based
delivery systems at a higher partitioning coefficient, whereas drugs with lower partitioning
coefficients may be more susceptible to hydrolysis or oxidation in those systems. Nevertheless, a
higher partitioning coefficient also affects the biocompatibility as previously mentioned.
Multiple scientific studies have shown the effect of partitioning coefficient on drug delivery. For
instance, a study conducted by Zhu in 2019 investigated the effect of partition coefficient on the
distribution of vinorelbine, an antineoplastic drug used for the treatment of various types of cancer
where the researchers prepared vinorelbine liposomes with different lipid compositions and
evaluated their pharmacokinetic profiles in rats and the results proved that the partition coefficient
of vinorelbine was significantly higher in the liposomes containing high amounts of cholesterol
and sphingomyelin compared to the liposomes containing only phospholipids. It was concluded
that increasing the partition coefficient of vinorelbine can enhance its accumulation in tumor
tissues and improve its antitumor efficacy. Another study was also conducted by Chen in 2019 that
investigated the effect of partition coefficient on the pharmacokinetics of ibuprofen. The results
showed that a higher partition coefficient led to a higher area under the concentration-time curve
17
Du J, Tang H, Zhang X, Jing X. Chapter 2 - Emulsions for Drug Delivery. In: Grumezescu AM, editor. Emulsions. William
Andrew Publishing; 2016. p. 25-64.
18 Mohsin K, Shahba AA, Alanazi FK. Development of controlled release lipid-based nanoparticles of pentoxifylline by BoxBehnken design for the management of peripheral arterial occlusive disease. A
Abdelbary, G. A., El-Gendy, N. A., & Youssef, A. M. (2012). Nanoparticles for enhancement of oral bioavailability of tadalafil:
preparation and in vitro and in vivo evaluation. International Journal of Nanomedicine, 7, 3027–3038.
https://doi.org/10.2147/ijn.s33394
Chen, Y., Liu, X., Wang, Y., Liu, X., Zhao, M., Zhou, X., … Wu, Y. (2019). The influence of partition coefficient on the
pharmacokinetics and analgesic efficacy of ibuprofen. European Journal of Pharmaceutical Sciences, 137, 104985.
https://doi.org/10.1016/j.ejps.2019.104985
Su, P., Li, S., Chen, S., Li, H.,
5
(AUC) and longer half-life. Similarly, a study by Su in 2019 found that the partition coefficient
affected the cellular uptake and cytotoxicity of curcumin in breast cancer cells19.
Moreover, a study conducted by Zhang et al. (2020) investigated the combined effect of particle
size and partition coefficient on the oral bioavailability of baicalin, a flavonoid with antiinflammatory and anticancer activities. The researchers prepared baicalin nanoparticles with
different particle sizes and surface modifications and evaluated their pharmacokinetic profiles in
rats. The results showed that the baicalin nanoparticles with small particle size and high partition
coefficient exhibited significantly higher bioavailability compared to the larger nanoparticles and
those with low partition coefficient. The authors concluded that optimizing both particle size and
partition coefficient can improve the oral bioavailability and therapeutic efficacy of baicalin20.
Zhu, L., Xu, X., Wang, Y., Guo, L., Huang, J., Zhao, J., … Zhang, Z. (2019). Liposomes containing cholesterol and
sphingomyelin enhance the pharmacokinetic profile and anti-tumor efficacy of vinorelbine. International Journal of Pharmaceutics,
556, 82–90.
20 Zhang, Y., He, X., Zhou, J., Zhang, Y., & Li, J. (2020). Combined effects of particle size and partition coefficient on the oral
bioavailability of baicalin nanocrystals with different surface modifications. International Journal of Nanomedicine, 15, 4177–
4188.
19
6
Conclusion
In conclusion, particle size and partitioning coefficient are essential factors that affect drug
delivery. Smaller particle sizes lead to faster drug absorption and higher bioavailability, while a
high partition coefficient indicates a higher tendency to accumulate in adipose tissue, taking into
consideration the aqueous solubility and permeability as they are a main factor of the drug delivery
system. Understanding the effect of these factors is crucial in optimizing drug delivery and
ensuring the desired therapeutic outcomes. Future research should focus on developing drug
delivery systems that take into account the particle size and partitioning coefficient of drugs to
improve their effectiveness and safety. In addition, the use of nanoparticles as a drug delivery
system shows promise for crossing the BBB and delivering drugs to the brain. However, further
research is needed to optimize nanoparticle design and ensure their safety and efficacy
for clinical use.
7
References
Chackalamannil,S, Rotella, D, Ward, S.(2017) Comprehensive Medicinal Chemistry III.
Available at: https://www.sciencedirect.com/referencework/9780128032015/comprehensivemedicinal-chemistry-iii (Downloaded: 9 April 2023)
K.S. Yadav, D.C. Dalal. (15 June 2021) The heterogeneous multiscale method to study particle
size and partitioning effects in drug delivery. Available at:
https://www.sciencedirect.com/science/article/abs/pii/S0898122121001000
(Accessed: 9 April 2023)
Climent, E, Benaiges, D, Pedro-Botet, J. (20 May 2021) Hydrophilic or Lipophilic Statins?
Available at:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172607/#:~:text=The%20classification%20of
%20drugs%20as,is%20greater%20in%20hydrophilic%20medications
(Accessed: 9 April 2023)
Grumezescu, A.M. (2018) Drug Targeting and Stimuli Sensitive Drug Delivery Systems.
Available at: https://www.sciencedirect.com/book/9780128136898/drug-targeting-and-stimulisensitive-drug-delivery-systems
(Downloaded: 9 April 2023)
Islam, M.A., Barua, S. & Barua, D. A. (25 November 2017). Multiscale modeling study of
particle size effects on the tissue penetration efficacy of drug-delivery nanoparticles. Available
at: https://bmcsystbiol.biomedcentral.com/articles/10.1186/s12918-017-0491-4#citeas
(Accessed: 9 April 2023)
Chingunpituk J. Particle size effect on the solubility and bioavailability of poorly soluble drugs:
theory and practice. Eur J Pharm Sci. 2016 Feb 15;89:181-94. doi: 10.1016/j.ejps.2016.04.014.
Epub 2016 Apr 16. PMID: 27091283.
Gao L, Zhang D, Chen M. Drug nanocrystals for the formulation of poorly soluble drugs and its
application as a potential drug delivery system. J Nanopart Res. 2008;10(5):845-62. doi:
10.1007/s11051-007-9309-9. Epub 2008 Jan 29. PMID: 18769649; PMCID: PMC2564352.
Nel A, Xia T, Mädler L, Li N. Toxic potential of materials at the nanolevel. Science. 2006 Jan
20;311(5761):622-7. doi: 10.1126/science.1114397. PMID: 16456071.
Abdelbary, G. A., El-Gendy, N. A., & Youssef, A. M. (2012). Nanoparticles for enhancement of
oral bioavailability of tadalafil: preparation and in vitro and in vivo evaluation. International
Journal of Nanomedicine, 7, 3027–3038.
8
Du J, Tang H, Zhang X, Jing X. Chapter 2 - Emulsions for Drug Delivery. In: Grumezescu AM,
editor. Emulsions. William Andrew Publishing; 2016. p. 25-64.
Mohsin K, Shahba AA, Alanazi FK. Development of controlled release lipid-based nanoparticles
of pentoxifylline by Box-Behnken design for the management of peripheral arterial occlusive
disease. A
Abdelbary, G. A., El-Gendy, N. A., & Youssef, A. M. (2012). Nanoparticles for enhancement of
oral bioavailability of tadalafil: preparation and in vitro and in vivo evaluation. International
Journal of Nanomedicine, 7, 3027–3038. https://doi.org/10.2147/ijn.s33394
Chen, Y., Liu, X., Wang, Y., Liu, X., Zhao, M., Zhou, X., … Wu, Y. (2019). The influence of
partition coefficient on the pharmacokinetics and analgesic efficacy of ibuprofen. European
Journal of Pharmaceutical Sciences, 137, 104985. https://doi.org/10.1016/j.ejps.2019.104985
Su, P., Li, S., Chen, S., Li, H.,
Zhu, L., Xu, X., Wang, Y., Guo, L., Huang, J., Zhao, J., … Zhang, Z. (2019). Liposomes
containing cholesterol and sphingomyelin enhance the pharmacokinetic profile and anti-tumor
efficacy of vinorelbine. International Journal of Pharmaceutics, 556, 82–90.
Zhang, Y., He, X., Zhou, J., Zhang, Y., & Li, J. (2020). Combined effects of particle size and
partition coefficient on the oral bioavailability of baicalin nanocrystals with different surface
modifications. International Journal of Nanomedicine, 15, 4177–4188.
Mallikarjuna Rao, Kishore Kumar, M., & Malla Reddy, C. (2011). A review on partition
coefficient and its determination methods. Der Pharmacia Lettre, 3(2), 267-276.
Huang, Y., Li, X., Li, Y., Li, H., & Li, G. (2018). Determination of the octanol/water partition
coefficient (logP) of triclosan by HPLC. Journal of Chemistry, 2018, 1-6.
Chen, X., Chen, Y., Wu, J., Li, Y., Hu, H., Liu, Y., ... & Li, W. (2018). Preparation of braintargeting rivastigmine-loaded solid lipid nanoparticles by co-grinding and ultrasonication
method. Colloids and Surfaces B: Biointerfaces, 162, 305-311.
Huile, G., Shu, C., & Jiang, Q. (2016). The blood-brain barrier (BBB) permeability in
Alzheimer's disease (AD) and the delivery of drugs to the brain. Asian Journal of Pharmaceutical
Sciences, 11(3), 303-312.
Kuo, Y. C., Lin, C. H., & Chen, C. C. (2017). Evaluation of blood-brain barrier permeability
using in vivo perfusion techniques: Quantitative analysis and determination of cutoff size.
BioMed Research International, 2017, 1-9.
Abbott, N. J., Patabendige, A. A., Dolman, D. E., Yusof, S. R., & Begley, D. J. (2010). Structure
and function of the blood-brain barrier. Neurobiology of Disease, 37(1), 13-25.
Bhushan, B., & Prajapati, R. (2017). Particle size analysis in pharmaceutical manufacturing
process. Journal of Pharmaceutical Research and Clinical Practice, 1(1),
9
Comments of Group B:
The students have explained the partitioning coefficient and particle size in drug delivery
in a simple yet accurate way and have given real life examples. However, one thing it
would greatly benefit from is the addition of more than one biological barrier in the
introduction. Moreover, more details are needed about emulsions and the active sites
in the discussion.
10