Presents the Definition, Classification, and Composition of Drug Emulsions.

CHAPTER 6

MEDICINAL EMULSION

TARGET

1. Describe the definition, classification, and composition of drug emulsions.

2. Analyze the advantages and disadvantages of drug emulsions

3. List the factors affecting the formation, stability and bioavailability of drug emulsions.

4. Describe common drug emulsion preparation techniques.

a

CONTENT

1. General

1.1. Distributed system

A dispersed system is a system in which one or more substances are dispersed in another substance.

other.

Dispersion is the term used to describe the preparation technique of mixing two immiscible phases together.

each other (different solubility).

Dispersed system consists of dispersed phase ( dispersed phase, internal phase) and dispersion medium (external phase).

Classification of dispersion systems according to the size of the dispersed phase:

Distributed system

Distributed system size
Homogeneous	< 1 nm
Heterogenous microorganism	1-100 nm
Heterogeneous	> 0.1 µm
Heteroplasmy	0.1 – 100 µm
Gross heterogeneity	100 µm

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• Presenting the Definition, Classification, and Composition of Drug Suspensions.
• Qos Assurance Methods for Multimedia Communications zt2i3t4l5ee zt2a3gs zt2a3ge zc2o3n4t5e6n7ts low. The EF PHB requires a sufficiently large number of output ports to provide low delay, low loss, and low jitter. EF PHBs can be implemented if the output port's bandwidth is sufficiently large, combined with small buffer sizes and other network resources dedicated to EF packets, to allow the router's service rate for EF packets on an output port to exceed the arrival rate λ of packets at that port. This means that packets with PHB EF are considered with a pre-allocated amount of output bandwidth and a priority that ensures minimum loss, minimum delay and minimum jitter before being put into operation. PHB EF is suitable for channel simulation, leased line simulation, and real-time services such as voice, video without compromising on high loss, delay and jitter values. Figure 2.10 Example of EF installation Figure 2.10 shows an example of an EF PHB implementation. This is a simple priority queue scheduling technique. At the edges of the DS domain, EF packet traffic is prioritized according to the values ​​agreed upon by the SLA. The EF queue in the figure needs to output packets at a rate higher than the packet arrival rate λ. To provide an EF PHB over an end-to-end DS domain, bandwidth at the output ports of the core routers needs to be allocated in advance to ensure the requirement μ > λ. This can be done by a pre-configured provisioning process. In the figure, EF packets are placed in the priority queue (the upper queue). With such a length, the queue can operate with μ > λ. Since EF was primarily used for real-time services such as voice and video, and since real-time services use UDP instead of TCP, RED is generally not suitable for EF queues because applications using UDP will not respond to random packet drop and RED will strip unnecessary packets. 2.2.4.2 Assured Forwarding (AF) PHB PHB AF is defined by RFC 2597. The purpose of PHB AF is to deliver packets reliably and therefore delay and jitter are considered less important than packet loss. PHB AF is suitable for non-real-time services such as applications using TCP. PHB AF first defines four classes: AF1, AF2, AF3, AF4. For each of these AF classes, packets are then classified into three subclasses with three distinct priority levels. Table 2.8 shows the four AF classes and 12 AF subclasses and the DSCP values ​​for the 12 AF subclasses defined by RFC 2597. RFC 2597 also allows for more than three separate priority levels to be added for internal use. However, these separate priority levels will only have internal significance. PHB Class PHB Subclass Package type DSCP AF4 AF41 Short 100010 AF42 Medium 100100 AF43 High 100110 AF3 AF31 Short 011010 AF32 Medium 011100 AF33 High 011110 AF2 AF21 Short 010010 AF22 Medium 010100 AF23 High 010110 AF1 AF11 Short 001010 AF12 Medium 001100 AF13 High 001110 Table 2.8 AF DSCPs The AF PHB ensures that packets are forwarded with a high probability of delivery to the destination within the bounds of the rate agreed upon in an SLA. If AF traffic at an ingress port exceeds the pre-priority rate, which is considered non-compliant or “out of profile”, the excess packets will not be delivered to the destination with the same probability as the packets belonging to the defined traffic or “in profile” packets. When there is network congestion, the out of profile packets are dropped before the in profile packets are dropped. When service levels are defined using AF classes, different quantity and quality between AF classes can be realized by allocating different amounts of bandwidth and buffer space to the four AF classes. Unlike EF, most AF traffic is non-real-time traffic using TCP, and the RED queue management strategy is an AQM (Adaptive Queue Management) strategy suitable for use in AF PHBs. The four AF PHB layers can be implemented as four separate queues. The output port bandwidth is divided into four AF queues. For each AF queue, packets are marked with three “colors” corresponding to three separate priority levels. In addition to the 32 DSCP 1 groups defined in Table 2.8, 21 DSCPs have been standardized as follows: one for PHB EF, 12 for PHB AF, and 8 for CSCP. There are 11 DSCP 1 groups still available for other standards. 2.2.5.Example of Differentiated Services We will look at an example of the Differentiated Service model and mechanism of operation. The architecture of Differentiated Service consists of two basic sets of functions: Edge functions: include packet classification and traffic conditioning. At the inbound edge of the network, incoming packets are marked. In particular, the DS field in the packet header is set to a certain value. For example, in Figure 2.12, packets sent from H1 to H3 are marked at R1, while packets from H2 to H4 are marked at R2. The labels on the received packets identify the service class to which they belong. Different traffic classes receive different services in the core network. The RFC definition uses the term behavior aggregate rather than the term traffic class. After being marked, a packet can be forwarded immediately into the network, delayed for a period of time before being forwarded, or dropped. We will see that there are many factors that affect how a packet is marked, and whether it is forwarded immediately, delayed, or dropped. Figure 2.12 DiffServ Example Core functionality: When a DS-marked packet arrives at a Diffservcapable router, the packet is forwarded to the next router based on Per-hop behavior is associated with packet classes. Per-hop behavior affects router buffers and the bandwidth shared between competing classes. An important principle of the Differentiated Service architecture is that a router's per-hop behavior is based only on the packet's marking or the class to which it belongs. Therefore, if packets sent from H1 to H3 as shown in the figure receive the same marking as packets from H2 to H4, then the network routers treat the packets exactly the same, regardless of whether the packet originated from H1 or H2. For example, R3 does not distinguish between packets from h1 and H2 when forwarding packets to R4. Therefore, the Differentiated Service architecture avoids the need to maintain router state about separate source-destination pairs, which is important for network scalability. Chapter Conclusion Chapter 2 has presented and clarified two main models of deploying and installing quality of service in IP networks. While the traditional best-effort model has many disadvantages, later models such as IntServ and DiffServ have partly solved the problems that best-effort could not solve. IntServ follows the direction of ensuring quality of service for each separate flow, it is built similar to the circuit switching model with the use of the RSVP resource reservation protocol. IntSer is suitable for services that require fixed bandwidth that is not shared such as VoIP services, multicast TV services. However, IntSer has disadvantages such as using a lot of network resources, low scalability and lack of flexibility. DiffServ was born with the idea of ​​solving the disadvantages of the IntServ model. DiffServ follows the direction of ensuring quality based on the principle of hop-by-hop behavior based on the priority of marked packets. The policy for different types of traffic is decided by the administrator and can be changed according to reality, so it is very flexible. DiffServ makes better use of network resources, avoiding idle bandwidth and processing capacity on routers. In addition, the DifServ model can be deployed on many independent domains, so the ability to expand the network becomes easy. Chapter 3: METHODS TO ENSURE QoS FOR MULTIMEDIA COMMUNICATIONS In packet-switched networks, different packet flows often have to share the transmission medium all the way to the destination station. To ensure the fair and efficient allocation of bandwidth to flows, appropriate serving mechanisms are required at network nodes, especially at gateways or routers, where many different data flows often pass through. The scheduler is responsible for serving packets of the selected flow and deciding which packet will be served next. Here, a flow is understood as a set of packets belonging to the same priority class, or originating from the same source, or having the same source and destination addresses, etc. In normal state when there is no congestion, packets will be sent as soon as they are delivered. In case of congestion, if QoS assurance methods are not applied, prolonged congestion can cause packet drops, affecting service quality. In some cases, congestion is prolonged and widespread in the network, which can easily lead to the network being "frozen", or many packets being dropped, seriously affecting service quality. Therefore, in this chapter, in sections 3.2 and 3.3, we introduce some typical network traffic load monitoring techniques to predict and prevent congestion before it occurs through the measure of dropping (removing) packets early when there are signs of impending congestion. 3.1. DropTail method DropTail is a simple, traditional queue management method based on FIFO mechanism. All incoming packets are placed in the queue, when the queue is full, the later packets are dropped. Due to its simplicity and ease of implementation, DropTail has been used for many years on Internet router systems. However, this algorithm has the following disadvantages: − Cannot avoid the phenomenon of “Lock out”: Occurs when 1 or several traffic streams monopolize the queue, making packets of other connections unable to pass through the router. This phenomenon greatly affects reliable transmission protocols such as TCP. According to the anti-congestion algorithm, when locked out, the TCP connection stream will reduce the window size and reduce the packet transmission speed exponentially. − Can cause Global Synchronization: This is the result of a severe “Lock out” phenomenon. Some neighboring routers have their queues monopolized by a number of connections, causing a series of other TCP connections to be unable to pass through and simultaneously reducing the transmission speed. After those monopolized connections are temporarily suspended, Once the queue is cleared, it takes a considerable amount of time for TCP connections to return to their original speed. − Full Queue phenomenon: Data transmitted on the Internet often has an explosion, packets arriving at the router are often in clusters rather than in turn. Therefore, the operating mechanism of DropTail makes the queue easily full for a long period of time, leading to the average delay time of large packets. To avoid this phenomenon, with DropTail, the only way is to increase the router's buffer, this method is very expensive and ineffective. − No QoS guarantee: With the DropTail mechanism, there is no way to prioritize important packets to be transmitted through the router earlier when all are in the queue. Meanwhile, with multimedia communication, ensuring connection and stable speed is extremely important and the DropTail algorithm cannot satisfy. The problem of choosing the buffer size of the routers in the network is to “absorb” short bursts of traffic without causing too much queuing delay. This is necessary in bursty data transmission. The queue size determines the size of the packet bursts (traffic spikes) that we want to be able to transmit without being dropped at the routers. In IP-based application networks, packet dropping is an important mechanism for indirectly reporting congestion to end stations. A solution that prevents router queues from filling up while reducing the packet drop rate is called dynamic queue management. 3.2. Random elimination method – RED 3.2.1 Overview RED (Random Early Detection of congestion; Random Early Drop) is one of the first AQM algorithms proposed in 1993 by Sally Floyd and Van Jacobson, two scientists at the Lawrence Berkeley Laboratory of the University of California, USA. Due to its outstanding advantages compared to previous queue management algorithms, RED has been widely installed and deployed on the Internet. The most fundamental point of their work is that the most effective place to detect congestion and react to it is at the gateway or router. Source entities (senders) can also do this by estimating end-to-end delay, throughput variability, or the rate of packet retransmissions due to drop. However, the sender and receiver view of a particular connection cannot tell which gateways on the network are congested, and cannot distinguish between propagation delay and queuing delay. Only the gateway has a true view of the state of the queue, the link share of the connections passing through it at any given time, and the quality of service requirements of the traffic flows. The RED gateway monitors the average queue length, which detects early signs of impending congestion (average queue length exceeding a predetermined threshold) and reacts appropriately in one of two ways: − Drop incoming packets with a certain probability, to indirectly inform the source of congestion, the source needs to reduce the transmission rate to keep the queue from filling up, maintaining the ability to absorb incoming traffic spikes. − Mark “congestion” with a certain probability in the ECN field in the header of TCP packets to notify the source (the receiving entity will copy this bit into the acknowledgement packet). Figure 3. 1 RED algorithm The main goal of RED is to avoid congestion by keeping the average queue size within a sufficiently small and stable region, which also means keeping the queuing delay sufficiently small and stable. Achieving this goal also helps: avoid global synchronization, not resist bursty traffic flows (i.e. flows with low average throughput but high volatility), and maintain an upper bound on the average queue size even in the absence of cooperation from transport layer protocols. To achieve the above goals, RED gateways must do the following: − The first is to detect congestion early and react appropriately to keep the average queue size small enough to keep the network operating in the low latency, high throughput region, while still allowing the queue size to fluctuate within a certain range to absorb short-term fluctuations. As discussed above, the gateway is the most appropriate place to detect congestion and is also the most appropriate place to decide which specific connection to report congestion to. − The second thing is to notify the source of congestion. This is done by marking and notifying the source to reduce traffic. Normally the RED gateway will randomly drop packets. However, if congestion If congestion is detected before the queue is full, it should be combined with packet marking to signal congestion. The RED gateway has two options: drop or mark; where marking is done by marking the ECN field of the packet with a certain probability, to signal the source to reduce the traffic entering the network. − An important goal that RED gateways need to achieve is to avoid global synchronization and not to resist traffic flows that have a sudden characteristic. Global synchronization occurs when all connections simultaneously reduce their transmission window size, leading to a severe drop in throughput at the same time. On the other hand, Drop Tail or Random Drop strategies are very sensitive to sudden flows; that is, the gateway queue will often overflow when packets from these flows arrive. To avoid these two phenomena, gateways can use special algorithms to detect congestion and decide which connections will be notified of congestion at the gateway. The RED gateway randomly selects incoming packets to mark; with this method, the probability of marking a packet from a particular connection is proportional to the connection's shared bandwidth at the gateway. − Another goal is to control the average queue size even without cooperation from the source entities. This can be done by dropping packets when the average size exceeds an upper threshold (instead of marking it). This approach is necessary in cases where most connections have transmission times that are less than the round-trip time, or where the source entities are not able to reduce traffic in response to marking or dropping packets (such as UDP flows). 3.2.2 Algorithm This section describes the algorithm for RED gateways. RED gateways calculate the average queue size using a low-pass filter. This average queue size is compared with two thresholds: minth and maxth. When the average queue size is less than the lower threshold, no incoming packets are marked or dropped; when the average queue size is greater than the upper threshold, all incoming packets are dropped. When the average queue size is between minth and maxth, each incoming packet is marked or dropped with a probability pa, where pa is a function of the average queue size avg; the probability of marking or dropping a packet for a particular connection is proportional to the bandwidth share of that connection at the gateway. The general algorithm for a RED gateway is described as follows: [5] For each packet arrival Caculate the average queue size avg If minth ≤ avg < maxth div.maincontent .s1 { color: black; font-family:"Times New Roman", serif; font-style: normal; font-weight: normal; text-decoration: none; font-size: 15pt; } div.maincontent .s2 { color: black; font-family:"Times New Roman", serif; font-style: normal; font-weight: bold; text-decoration: none; font-size: 15pt; } div.maincontent .p { color: black; font-family:"Times New Roman", serif; font-style: normal; font-weight: normal; text-decoration: none; font-size: 14pt; margin:0pt; } div.maincontent p { color: black; font-family:"Times New Roman", serif; font-style: normal; font-weight: normal; text-decoration: none; font-size: 14pt; margin:0pt; } div.maincontent .s3 { color: black; font-family:"Times New Roman", serif; font-style: normal; font-weight: bold; text-decoration: none; font-size: 14pt; } div.maincontent .s4 { color: black; font-family:"Times New Roman", serif; font-style: normal; font-weight: normal; text-decoration: none; font-size: 14pt; } div.maincontent .s5 { color: black; font-family:"Times New Roman", serif; font-style: italic; font-weight: normal; text-decoration: none; font-size: 14pt; } div.maincontent .s6 { color: black; font-family:"Times New Roman", serif; font-style: italic; font-weight: bold; text-decoration: none; font-size: 14pt; } div.maincontent .s7 { color: black; font-family:Wingdings; font-style: normal; font-weight: normal; text-decoration: none; font-size: 14pt; } div.maincontent .s8 { color: black; font-family:Arial, sans-serif; font-style: italic; font-weight: bold; text-decoration: none; font-size: 15pt; } div.maincontent .s9 { color: black; font-family:"Times New Roman", serif; font-style: normal; font-weight: bold; text-decoration: none; font-size: 14pt; } div.maincontent .s10 { color: black; font-family:"Times New Roman", serif; font-style: normal; font-weight: normal; text-decoration: none; font-size: 9pt; vertical-align: 6pt; } div.maincontent .s11 { color: black; font-family:"Times New Roman", serif; font-style: normal; font-weight: normal; text-decoration: none; font-size: 13pt; } div.maincontent .s12 { color: black; font-family:"Times New Roman", serif; font-style: normal; font-weight: normal; text-decoration: none; font-size: 10pt; } div.maincontent .s13 { color: black; font-family:"Times New Roman", serif; font-style: normal; font-weight: normal; text-d
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1.2. Definition

Emulsion is a heterogeneous mechanical dispersion system formed from two immiscible liquids. In which one liquid is the dispersed phase (internal phase, discontinuous phase) dispersed into the second liquid is the dispersion medium (external phase, continuous phase) in the form of mechanical particles with sizes from 0.1 to tens of micrometers.

A drug emulsion is a liquid or soft dosage form for oral, injectable or topical use, prepared by using emulsifiers to mix two immiscible liquids conventionally called:

Oil (including oils, fats, waxes, essential oils, resins and water-insoluble pharmaceutical substances) and Water (including distilled water, aromatic water, decoctions, infusions or aqueous solutions of pharmaceutical substances, etc.).

1.3. Components of emulsion

The composition of emulsions in general and drug emulsions in particular consists of two components: dispersion medium and dispersed phase.

Emulsions have a very low ratio of dispersed phase to dispersion medium, just need to combine dispersed phase and dispersion medium with very small dispersion force can also create emulsion. But for drug emulsions (and other types of emulsions - cosmetics, food ...) in reality, the ratio of dispersed phase is very high, to form emulsions and maintain their stability within the specified time limit, in addition to the two phases of the emulsion, there must be a third component which is emulsifier - stabilizer.

1.4. Types of emulsions

In reality there are only two types of emulsions:

- Oil in water (symbol: D/N): dispersed phase is Oil and dispersion medium is

Water. Oil.

- Water in oil (symbol: N/D): the dispersed phase is Water and the dispersion medium is In addition, in pharmaceutical practice, people often prepare double emulsions,

where the dispersed phase is a D/N or W/D emulsion:

+ W/D/N emulsion: the dispersed phase is W/D emulsion and the dispersion medium is

water.

+ D/N/D type emulsion: the dispersed phase is a D/N type emulsion and the dispersion medium is

oil is the oil.

In terms of properties, N/D emulsions are non-polar substances and D/N emulsions are polar substances, so double emulsions are essentially just one of two types of D/N or N/D emulsions.

Figure 6.1. Types of emulsions: (1) W/D, (2) D/N, (3) D/N/D, (4) N/D/N Oil : Water

1.5. Emulsion classification

1.5.1. By origin

- Natural emulsions: available in nature such as animal milk, oil seeds.

- Artificial emulsion: using emulsifiers and dispersion force to create emulsion.

1.5.2. According to the ratio of dispersed phase and dispersion medium

- Dilute emulsion: has internal phase concentration ≤ 2%.

- Concentrated emulsion: has internal phase concentration > 2%.

In fact, most drug emulsions are concentrated emulsions with a dispersed phase concentration of 10-15%, in some cases it is 80-90%.

1.5.3. By level of dispersion

Divided into 3 types:

- Microemulsion: very small particle size, almost equal to heterogeneous microcolloid particles.

- Fine emulsion: particle size from 0.5 - 1.0 micrometers.

- Coarse emulsion: particle size from several micrometers or more.

1.5.4. By emulsion type

- D/N type emulsion.

- N/D type emulsion.

- D/N/D type emulsion.

- N/D/N type emulsion.

1.5.5. By route of administration

 Emulsion used in

- Infusion emulsion: both types of emulsion can be used for intramuscular injection, only D/N emulsion with particle size smaller than 0.5 micrometers can be used for infusion. Do not inject drug emulsion directly into the spine regardless of whether the emulsion is D/N or N/D.

- Oral emulsions: only use D/N type emulsions, usually potio emulsions.

 External emulsion: for application, rubbing, and covering, both emulsions can be used. However, D/N emulsion is easier to wash off and does not stain clothes.

1.6. Advantages and disadvantages of emulsion

1.6.1. Advantages

- Emulsions allow easy mixing of insoluble liquid drugs or solid drugs that are only soluble in one type of solvent.

- D/N emulsion oral medication masks unpleasant taste and reduces irritation to the digestive tract.

- Injectable drugs using D/N emulsions are prepared from substances that are poorly soluble or insoluble in water for intravenous injection. These emulsions have the properties of a drug solution and therefore do not cause vascular occlusion.

- Ointments, rubs: soft, smooth emulsion form, soothing to the skin and mucous membranes, less greasy, less dirty to the skin and clothes. In addition, it is also possible to choose the location of shallow or deep action when prepared in the form of suitable emulsion D/N or N/D.

1.6.2. Disadvantages

- It is a non-homogeneous mechanical dispersion so it is not stable.

- Requires certain equipment, bartenders understand and master the technique.

2. Emulsifiers commonly used in emulsion preparation

2.1. Emulsifier requirements

The ideal emulsifier used in drug emulsions must not only be a strong emulsifier but also a good excipient. Therefore, it must meet the following requirements:

- Has the ability to strongly emulsify many drugs or additives and is used in very small quantities.

- Durable, less affected by pH, temperature, electrolytes, desiccants, bacteria, and mold.

- Does not cause physical or chemical incompatibility with pharmaceutical ingredients or additives found in the drug.

- Has no specific pharmacological effect, if any, must act synergistically with other drugs.

matter.

- No color, odor or pleasant taste.

2.2. Commonly used emulsifiers

2.2.1. Natural emulsifiers

Carbohydrates

Commonly used are gums, pectins, agar, starch, mucilage, alginates, etc. These are substances with large molecules that easily dissolve or swell in water to create a colloidal solution with high viscosity. These substances are often called hydrophilic colloids, have an emulsifying effect for D/N emulsions, and are also substances that have a stabilizing effect.

General advantages: colorless, tasteless, has no specific pharmacological effects, soothes the gastrointestinal mucosa, covers up the unpleasant taste of the drug. Acts as a stable emulsifier in emulsions and as a permeating agent to turn hydrophilic solid drugs into hydrophilic drugs in oral suspensions.

Disadvantages: susceptible to damage or deterioration by mold, surfactants, and desiccants at high concentrations.

- Gum arabic

It is a product of many types of acacia with complex composition, at room temperature, completely soluble in an amount of water about twice the amount of gum, the solution has a slightly acidic pH and the gum micelles are negatively charged.

Used to prepare potions because in addition to its general advantages, it also has the advantage of being easily soluble in water at room temperature and has the ability to reduce surface tension.

The ratio of gum used to emulsify liquid oil is about 25 - 50% compared to the amount of oil.

The ratio of gum used to emulsify the drug depends on the density: small density (essential oil) the ratio of gum is equal to the drug, medium density (creozol) the ratio of gum is 50% compared to the drug, large density the ratio of gum is 2 times the amount of drug.

- Adagant gum

It is a product of the Astraglus gumifera plant of the butterfly family with complex composition.

At room temperature, it absorbs water and swells slowly. It swells quickly at high temperatures. To dissolve easily, the gum should be moistened with alcohol and glycerin first. It is easily precipitated by alcohol, electrolytes and other water-absorbing substances at high concentrations.

Gum adagant solution has 50 times more viscosity than arabic at the same concentration. Concentration > 2% when cooled forms a gel with no emulsifying ability.

Adagant gum does not have the ability to reduce surface tension but forms a high viscosity colloidal solution with water, so it is used as a stabilizer, combined with gum arabic to prepare emulsions. The ratio of adagant gum to arabic is 1/10, higher than that will affect the emulsifying ability of gum arabic. It is also used as a wetting agent in preparing suspensions.

oil).

Adagant gum is used to prepare emulsions containing low density drugs (crystals).

Like gum arabic, gum Adagant is used as a penetrant in the preparation of

Adagant goat gum is precipitated by alcohol, electrolytes and dehydrating agents at high temperatures.

- Jelly

Is a product of some types of seaweed with complex composition.

Agar does not have the ability to reduce surface tension but creates a highly viscous colloidal solution with water, so it should be used in combination with gum arabic.

Jelly has the effect of softening, increasing stool volume and stimulating intestinal motility, so it is used to prepare laxative and purgative emulsions.

At room temperature, it absorbs water and swells and dissolves at boiling temperature. At concentrations >1%, when cooled, the jelly will form a gel and lose its emulsifying effect. Jelly only has an emulsifying effect in a slightly alkaline environment. Note that jelly is easily precipitated by tannin, by alcohol from 50% or more and electrolytes at high concentrations.

Saponins

Are heteroside molecules consisting of two parts: a nonpolar lipophilic aglycol and a polar hydrophilic sugar.

Are surfactants with real emulsifying and strong penetrating ability. Easily soluble in alcohol and water, they are emulsifiers that create D/N emulsions.

Disadvantages: causes blood destruction, irritation of digestive mucosa, so it can only be used to prepare emulsions and suspensions for external use (apply, rub).

To make an emulsifier and absorbent, use a tincture made from medicinal herbs containing saponin (ratio 1/5 60o alcohol ) in equal amounts with water-based medicinal ingredients.

Proteins

Proteins commonly used as emulsifiers include some substances such as gelatin, milk, egg yolks and derivatives. These substances have large molecules that are easily dissolved or dispersed in water to form a colloidal solution with high viscosity (hydrophilic colloidal substances) and are emulsifiers that create D/N emulsions. They have strong emulsifying ability but are easily decomposed, spoiled, cannot be preserved for a long time, and easily coagulated by temperature.

- Gelatin

Is a product of incomplete hydrolysis of collagen found in the skin, tendons and bones of animals. Usually found in the form of thin sheets or light yellow flexible pieces.

At room temperature, gelatin absorbs water and swells, but only dissolves at high temperatures.

boil

Gelatin as an emulsifier is prepared at pH = 7 - 8 to have an emulsifying effect.

strong chemical

When using in combination with other substances, pay attention to the charge.

The 1% use rate in liquid form requires a strong dispersion medium to achieve results.

fruit.

- Gelactose

Is a completely hydrolyzed product of gelatin.

Used as an emulsifier to replace gum arabic, similar concentration and usage.

- Milk

It is a natural emulsion containing 3% casein so it has emulsifying ability, use condensed milk or powdered milk.

Ratio: One part emulsified milk powder to two parts oil mixture One part emulsified condensed milk to five parts oil mixture

Prone to mold, so only prepare emulsion for use within a few days.

- Casein

Made from milk and refined as an emulsifier.

Usually use Nacaseinate salt dissolved in water: one part emulsifying salt to 10 parts oil phase.

- Egg yolk

It is a concentrated emulsion containing a large proportion of protein emulsifiers, lecithin, and cholesterol, so it has strong emulsifying ability.

One egg yolk (10 – 15g) can emulsify 100 – 120ml of liquid oil; 50 – 60ml of essential oil or other liquid pharmaceuticals that do not dissolve in water.

Used to prepare nutritional emulsions and nutritional emulsions.

Sterols

Typically, cholesterol and its derivatives are abundant in lanolin (sheep wool wax), lard, fish oil, and egg yolks.

Composed of two parts: oil body and water body, it has surface activity and emulsifying and permeating properties.

The oil-based part is more dominant than the water-based part, so it is easily soluble in oil and is an emulsifier that creates N/D emulsions. It has the ability to emulsify twice as much water.

Cholestrol is extracted separately as an emulsifier and used at a ratio of 1 - 5% compared to pharmaceutical ingredients in ointments, rubs, suppositories, eggs, and oil injections.

There are also bile acids in the form of alkaline salts that are soluble in water and form emulsions.

D/N.

Phospholipids

Typically, lecithin is abundant in egg yolks and soybeans, which are emulsifying surfactants.

Strong chemical. Insoluble but easily dispersed in water, creating D/N emulsion.

Non-toxic, so it is widely used to prepare oral, injectable, and topical emulsions.

outside.

Easily oxidized by light, air, alkaline environment.

2.2.2. Synthetic and semi-synthetic emulsifiers

Synthetic and semi-synthetic emulsifiers are increasingly widely used because they have advantages over natural emulsifiers: strong and stable emulsifying effect, less affected by external factors such as pH, bacteria, and temperature.

In terms of emulsification mechanism, they can be classified into two large groups:

- Surfactants (true emulsifiers).

- Stable emulsifier.

Surfactants

These substances are obtained by synthesis or extraction from plant, animal, and mineral materials.

The common property of the group is the ability to adsorb on the phase interface and form a single layer, multi-molecular layer or oriented ions that change the polar nature of the surface and reduce the surface energy between the two phases.

Typical surfactants are amphiphilic compounds containing both hydrophilic and lipophilic parts in their molecules.

- The water body has an electrostatic dipole moment created by the COO-, SO2-, polyoxyethylene groups ... Usually contains nitrogen or phosphorus, sulfur.

- The oil body is usually a hydrocarbon radical that does not have a clear dipole moment, so its nature is similar to a non-polar or slightly polar environment. The hydrocarbon radical can be a straight chain or a ring (most commonly derivatives of benzene and naphthalene).

- Only surfactants whose molecules have two parts that are not balanced have the ability to reduce the surface tension of liquids and phases and as a result reduce the interfacial tension of the phases.

Surfactants used in pharmaceuticals include 4 groups:

- Cationic surfactant.

- Anionic surfactants.

- Amphoteric surfactant.

- Non-ionic surfactant.

The most common non-ionic surfactants are:

- Tween 20 (21, 40, 60, 61, 65, 80, 81)

- Span 20 (40, 60, 65. 80, 85)

- Fatty sugars: sorbester S-12 (-212, -312, -17, -217…).

- Mirj: mirj45 (49, 51, 52, 53, 59).

Esters of triglycerides with fatty acids : from 3 molecules of glycerin and 2 molecules of water, triglycerides are obtained. Esterification with fatty acids with carbon chains containing 16 - 18 carbon atoms at 200 o C. At room temperature, the physical state is like wax. Strong emulsifying effect. Esterification of 1 - 2 -OH groups of triglycerides will obtain emulsifiers for D/N emulsions. Esterification of 3 or more -OH groups will produce emulsifiers soluble in oil, for N/D emulsions.

 Stabilizing emulsifiers .

Poly oxyethylene glycols (PEG):

High molecular weight products polymerize oxyethylene with water. At room temperature, products with molecular weight 200 - 700 can be liquid like oil. Products with molecular weight > 1000 can be soft like vaseline to white like wax.

Easily soluble in water, solubility decreases as molecular weight increases, easily soluble in alcohol, organic solvents, insoluble in ether, fatty oils, mineral oils.

Advantage:

- Physical and chemical stability, no color, no taste, no specific pharmacological effects, non-toxic, less affected by mold and bacteria.

- Is a good stabilizer for emulsions, used to prepare suspensions, emulsions, and drug solutions.

Polyvinylic alcohols:

Are high molecular polymerization products of vinylic alcohol by hydrolysis of polyvinylic acetate. Ivory white powder, slightly moist, stable to light. Soluble in water, glycerin, insoluble in alcohol and other organic solvents.

It has the ability to increase viscosity, reduce surface tension of water, as a protective colloid with no pharmacological effect, significant specific taste, so it is used in the preparation of oral, injectable, and topical drug suspensions and emulsions.

Chemically inert, highly pure, sterilizable, suitable for the eye mucosa, helps to quickly restore eye damage, makes the drug contact longer with the eye mucosa, so it is good for use in eye drops.

The form used is polyvinylic alcohol with high viscosity, concentration 2 - 5%.

Cellulose derivatives:

Ethering some free OH groups in cellulose molecules with different substances will produce derivatives with many properties similar to natural glues (gums, mucus) but with the advantages of being pure, stable in a wider pH range, less affected by bacteria and mold, less affected by temperature so they can be sterilized without being damaged.

Used as an emulsifier to prepare emulsions, oral suspensions, used topically as an excipient in tablets, ointments (including eye drops).

Or use Methyl cellulose (MC, celacol), hydroxymethyl cellulose (Natrosol 250), carboxymethylcellulose (CMC)...

2.2.3. Solid emulsifiers in the form of small particles

Are solids that do not dissolve in water and oil in the form of very fine powder. To have an emulsifying effect, the size of the powder particles must be much smaller than the size of the dispersed phase particles of the emulsion.

The type of substance that is more permeable to water than oil will give a D/N emulsion, the type that is more permeable to oil than water will give a N/D emulsion.

If the emulsifier has the same ability to absorb oil and water, then whichever phase is mixed with the emulsifier first, that phase will be the dispersion medium.

Or use bentonite, vegum, hectorite, superfine cellulose powder.

3. Factors affecting the formation, stability and bioavailability of drug emulsions.

There are many factors that directly or indirectly influence the formation, stability and bioavailability of emulsions. We will consider only some of the main factors.

3.1. Effect of interfacial tension on phase separation

The formation of emulsion is always accompanied by the absorption of mechanical energy, the created surface carries free energy, which depends on the total contact surface area and the surface tension of the two phases. According to the expression:

Ε = δ.S where E: free surface energy (Nm)

δ: interfacial tension (N/m)