Chapter 6 Solid preparation In the last chapter, introduced powder technology (densities, noyes whitney, units of preparations, what units? Solid dispersions, ), Dr. Lei Luo 15730075066@sina.cn

Requirements To understand the definition, characteristics and preparation methods of powders, granules, capsules, drops and pills. (2) Master the preparation process, influencing factors and quality control of granules and capsules; (3) Master the prescription design of tablets, the classification and application of excipients, the process and equipment of tableting; (4) Master the quality evaluation of tablets.

Contents Powders 1 Granules 2 Capsules 3 Tablets 4 Drops and films 5

Solid preparation producing flow chart Powders Capsules Granules Tablets Reviewing 这是重点！膜剂和滴丸剂的工艺在之后介绍。散剂颗粒剂片剂胶囊剂，第一步，药物都是通过粉碎和过筛。然后通过和辅料混合，就制成了散剂。混合后通过造粒，就能形成颗粒剂。分别将散剂或颗粒剂灌装入胶囊内，就形成了胶囊剂。造粒以后通过压片的过程，就能形成片剂。

1. Powders 1.1 Definition Powders are mixtures of dry, fine, divided drugs and/or chemicals that may be intended for internal (oral) or external (topical) use. May be intended for internal use or external use, but most frequent use is external. Use as a dosage form is limited, but use in preparation of other dosage forms is extensive. 散剂，联想到粉体学 veterinary drugs 加复习固体制剂的环节，以及Noyes Whitney方程。 True density, bulk density 前面介绍了制备工艺，包括粉碎、过筛、混合、制粒的技术和机械。接下来给大家介绍具体的固体制剂，散剂。

Noyes-Whitney equation Dissolution rate: dC/dt=KS (CS-C) K=D/Vδ K- dissolution rate constant S- surface area of undissolved solid D- diffusion constant of drug CS- solubility in dissolution medium δ- Thickness of boundary layer C- concentration in medium V- Volume of dissolution medium

1.2 Administration routes Oral: oral powders, effervescent powders Inhalation: dry-powder as pulmonary DDS Nasal Topical: large open wound Ear powder Preparing for further treatment: suspension, syrup, oral drops, injection Oral powder administrate with water or other liquid or swallow directly Citric acid + sodium bicarbonate 肺 medication of asthma (salbutanol) or other disease

1.3 Advantages and disadvantages a) Chemically stable and long shelf-life b) Convenient for patients c) Orally powders fast dissolution d) Topical powders large spread area

1.3 Advantages and disadvantages a) Less convenient than tablets or capsules b) Hard to mask unpleasant taste c) Difficult to protect from atmospheric moisture or oxygen d) Not suitable for low dose (difficult measurement) e) Not suitable for drugs irritate or damage stomach

Divided Powders • Have generally fallen into disuse because of the ready availability of tablets and capsules. • Some commercial OTC products are packaged in similar unit-dose packets: –BC Headache Powders –Stanback Analgesic Powders

1.4 Packing The divided portions are each placed on a small piece of paper, which is then folded to enclose the medication (powder papers). Avoiding moisture or oxygen! Mengtuorock diarrhea

Notice for blending powders Low dosage or toxic drug－Equivalent multiplied Liquid or extract－Absorbent 1.1份小组分，5份大组份。取1份小组分和1份大组分，同时混合均匀，一边混合一边加入1份大组分混合均匀，如此倍量增加直至加完全大组分为止。2.处方中含有少量的液体成分，如挥发油、酊剂、流浸膏等，可利用处方中其他固体成分吸收。含有低共熔组分散剂，可先形成低共熔物，呈液态或半固体形态，再与其它固体粉末混匀或分别以固体粉末稀释低共熔组分，再轻轻混匀。

2. Granules Generally irregular in shape, as opposed to spherical. 2.1 Definition Prepared by agglomerating of smaller particles of powder. Generally irregular in shape, as opposed to spherical. Often in 4 to 12 mesh size, depending on application –May be dispensed in bulk as a dosage form for oral administration, e.g. as antacid, dietary supplement etc. –Widely used as an intermediate for making compressed tablets or filling into capsules 它是将药物与适宜的辅料配合而制成的颗粒状制剂,亦有压成块状的冲剂。一般按其在水中的溶解度分为

Why granules? Prevent powder segregation Size enlarge --- better flowability better compressibility than powders (binders) – advantage in making tablets or filling capsules (feeding of high-speed equipment) Less surface area – More stable to atmospheric moisture/oxygen – Less likely to cake in the container than powders – Reduce toxic dust during handling

Binders for wet granulation: PREGELAT Binders for wet granulation: PREGELAT. STARCH, STARCH, gelatin, PVP(polyvinylpyrrolidone), HPMC(hydroxypropylmethylcellulose) Moist mass-dough

Granulators Fluid-Bed High shear granulator

Fluid Bed Granulation Requires proper balance of inlet air temperature and feed rate. –For a given feed rate: Higher feed rates increases the ‘evaporative load’ and slows drying; tends to produce larger, denser and stronger granules Lower feed rates tend to produce smaller, friable granules –For a given inlet temperature Higher inlet air temperatures cause rapid evaporation of the binder solution and results in smaller, friable granules. Lower inlet temperatures, drying is slower (particles stay wetter longer); produces larger, denser, stronger granules.

Wet granulation is not practical for drugs sensitive to water or heat…

Dry Granulation Roller Compaction –Powder blend force between rollers to form a cake (“ribbon”) –Cake milled to form granules Dry binders. i.e. Microcrystalline cellulose Drug or fillers need cohesive property. Aspirin is commonly prepared into tablets after slugging, since it is hydrolyzed on exposure to moisture.

Effervescent Granulated Salts “Effervescent Salts” Effervescent granules contain medicinal substance usually in combination with sodium bicarbonate, citric acid and tartaric acid. Carbon dioxide forms with placed in water. Carbonation helps mask the unpleasant taste of drugs. Granular form (as opposed to power form) Wet method -moisten with “non-solvent,” e.g. 95% alcohol. Just enough water to granulate without causing effervescence. Dry (fusion) method -Requires use of citric acid monohydrate. Under carefully controlled conditions, heat to 93-104oF to liberate the water of crystallization from CA which then serves to moisten the powders for granulation.

Question Citric acid Tartaric acid Sodium bicarbonate NaHCO3

3. Capsules 3.1 Definition Capsule is a shell or a container prepared from gelatin containing one or more medicinal and/or inert substances. Hard Shell Capsules (Two pieces) Soft Shell Capsules (One piece)

Why gelatin? Non-toxic and widely used Gelatin is prepared by the hydrolysis of collagen, from animal skins and bones. Non-toxic and widely used Readily soluble in biological environment Decent film-forming material Solutions of high polymer concentration (40% w/v) Reversible change from a sol to a gel The wall thickness of a hard gelatin capsule is about 100 μm. at temperatures only a few degrees above ambient. This is in contrast to other films formed on dosage forms, where either volatile solvents or large quantities of heat are required to cause this change of state, e.g. tablet lm coating. These types of film are formed by spraying and have a structure that could be described as formed of overlapping plates, whereas the gelatin films are homogeneous in structure, which gives them their strength

Advantages （1）Odorless and tasteless （2）Stability (barrier to oxygen and moisture) （3） Easily swallow, improve bioavailability （4）Controlled drug release 4.根据胶囊壳的性质不同，可缓控释药 enteric

Disadvantages （1）The drugs which are hygroscopic absorb water from the capsule shell making it brittle and hence are not suitable for filling into capsules. （2）The concentrated solutions which require previous dilution are unsuitable for capsules because if administered as such lead to irritation of stomach. Hygroscopic 吸湿的

Bosch GKF 1500 Dosing Disc Machine Preparation Bosch GKF 1500 Dosing Disc Machine 90,000/hr 通过动画让大家了解。

Soft capsules Similar to hard gelatin shell, except plasticizer is incorporated (sorbitol, propylene glycol, glycerin) Usually filled with liquids or suspensions (dry solids are possible, including compressed tablets (“Geltabs”). VitE，Fish oil Omega3

Formulation for soft capsules Pure liquids, mixtures of miscible liquids, or solids dissolved or suspended in a liquid vehicle. Vehicles Water immiscible non-volatile liquids Vegetable oils Mineral oil not recommended Water-miscible, non-volatile liquids Low molecular weight PEG's Nonionic surfactants such as polysorbate 80 Miscible 可混溶的

Limitations of Liquid Contents Water cannot exceed 5% of contents pH must be between 2.5 and 7.5 Low molecular weight water soluble and volatile compounds must be excluded Aldehydes need excluded (Cause cross-linking) Contents must flow under gravity at < 35 通过动画让大家了解。

Rotary Die process

Quality consideration Ingredient specifications In-process testing Finished product testing Self reading on P609 Aulton’s Pharm 通过动画让大家了解。

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